The metabolic modulator PGC-1α in cancer Frédéric Bost, Lisa Kaminski

To cite this version:

Frédéric Bost, Lisa Kaminski. The metabolic modulator PGC-1α in cancer. American Journal of Cancer Research, e-Century Publishing, 2019, 9 (2), pp.198-211. ￿hal-03034295￿

HAL Id: hal-03034295 https://hal.archives-ouvertes.fr/hal-03034295 Submitted on 15 Dec 2020

HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Am J Cancer Res 2019;9(2):198-211 www.ajcr.us /ISSN:2156-6976/ajcr0085524

Review Article The metabolic modulator PGC-1α in cancer

Frederic Bost, Lisa Kaminski

Université Nice Côte d’Azur, Inserm, C3M, Centre Méditerranéen de Médecine Moléculaire (INSERM U1065), Nice, France Received September 14, 2018; Accepted September 21, 2018; Epub February 1, 2019; Published February 15, 2019

Abstract: The peroxisome proliferator-activated gamma coactivator 1 alpha (PGC-1α) is a central modulator of cell metabolism. It regulates mitochondrial biogenesis and oxidative metabolism. Modifications and adaptations in cellular metabolism are hallmarks of cancer cells, thus, it is not surprising that PGC-1α plays a role in cancer. Sev- eral recent articles have shown that PGC-1α expression is altered in tumors and metastasis in relation to modifica- tions in cellular metabolism. The potential uses of PGC-1α as a therapeutic target and a biomarker of the advanced form of cancer will be summarized in this review.

Keywords: PGC1 alpha, prostate cancer, melanoma, breast cancer, pancreatic cancer, metabolism, mitochondria

Introduction olism. It is therefore not surprising that altera- tions in the activity and expression of PGC-1α Modifications and adaptations in cellular me- are associated with many diseases in different tabolism are hallmarks of cancer cells. After tissues. It is well established that PGC-1α is the pioneering discovery, made by Otto War- implicated in diabetes, neurodegeneration and burg, showing that cancer cells preferentially cardiovascular disease [8, 9], but several recent use glycolysis to meet their energetic needs, articles, discussed below, have also revealed several studies have shown that cancer cells that PGC-1α plays an important role in cancer. have an altered metabolism compared to nor- In this review, after an overview of PGC-1α, we mal cells. Recent findings have elucidated the will discuss the latest results concerning the metabolic changes, also termed metabolic re- role of this coactivator in tumorigenesis and the programming, occurring in cancer cells in re- formation of metastases. sponse to environmental challenges such as hypoxia, nutrient scarcity, increased radical PGC-1α is a transcriptional coactivator and a oxygen species (ROS), or pH modifications [1, member of the PGC-1 2]. These metabolic adaptations confer resis- tance to apoptosis and are required to sustain The PGC-1 family is composed of three mem- rapid cell proliferation, migration and invasion. bers, PGC-1α, PGC-1β and PRC (PGC-1-related Thus, interfering with cancer cell metabolism coactivator), which share common structural with drugs such as metformin (an inhibitor of features and modes of action (Figure 1). The the complex 1 of the mitochondrial respiratory first member of the PGC-1 family, PGC-1α, was chain), or 2-deoxyglucose (2-DG; an inhibitor of identified in the late 1990s and found to in- glycolysis), has been shown to decrease tumor teract with the peroxisome proliferator-activat- growth and induce apoptosis in several cancer ed receptor-γ (PPARγ) in cells types [3-7]. brown adipose tissue, a tissue rich in mitoch- One of the major and well-described modula- ondria and specialized in thermogenesis [10]. tors of cell metabolism is a member of the per- PGC-1α is a transcriptional coactivator whose oxisome proliferator-activated receptor gamma expression is induced in response to cold expo- coactivator 1 (PGC-1) transcriptional co-activa- sure in brown adipose tissue, and in skeletal tor family: PGC-1α. PGC-1α is implicated in muscle in association with the expression of mitochondrial biogenesis and oxidative metab- decoupling mitochondrial proteins (UCPs: un- PGC-1α and cancer

They bind to various transc- ription factors and nuclear receptors that recognize spe- cific sequences in their targ- et . While other tran- scriptional coactivators pos- sess intrinsic histone acetyl- activity that fa- cilitates chromatin remodel- ing and transcription, members of the PGC-1 fami- ly lack enzymatic activity. Therefore, PGC-1 coactivators exert their modulatory func- Figure 1. The PGC-1 protein family members. Schematic representation of tion on gene transcription by the three members of the PGC-1 family, indicating their different regions and acting as an anchor platform the % of homology between each member in the N and C-terminal region of for other proteins with histo- the co-activators. ne acetyltransferase activity and by promoting the assem- coupling proteins). PGC-1β is the closest homo- bly of transcriptional machinery to trigger gene logue of PGC-1α. They share high sequence transcription. identity [11, 12], especially across several dis- tinct domains including an N-terminal activa- The N-terminal region of PGC-1α has several tion domain (40% homology), a central regula- LXXLL leucine-rich motifs, also called NR boxes, tory domain (35%) and a C-terminal RNA binding which are crucial for interactions between PGC- domain (48%). Both coactivators are highly 1α and a wide variety of nuclear receptors and expressed in oxidative tissues such as brown transcription factors (Figure 1). Among these adipose tissue, heart, kidney, skeletal muscle transcription factors, PPARα [18], the estrogen and brain [13]. PRC is ubiquitously expressed receptor (ER) [19], α (RXRα) and shares lower levels of homology with the [20], the (GR) [21], the two other members of the family (Figure 1) [14]. hepatocyte nuclear factor-4 α (HNF4α), nuclear Of note, splice variants of PGC-1α (NT-PGC-1α respiratory factor 1 and 2 (NRF1/NRF), and ste- and PGC-1α 1-4) have been identified in skele- rol regulatory element-binding proteins 1 and 2 tal muscle and their role and function remain (SREBP1/2) are known to regulate the expres- poorly described [15]. sion of genes implicated in several functions of cellular metabolism (Table 1). The N-terminus of these coactivators contains a transcriptional activation domain as well as PGC-1α is a metabolic sensor of environmen- an important motif for interactions with nucl- tal stresses ear receptors: the leucine-rich LXXLL motif [16]. The C-terminal domain has the highest The expression and activity of PGC-1α are con- homology between the three PGC-1 coactiva- trolled by environmental and physiological stim- tors and includes an RNA recognition and bind- uli. Temperature, more specifically the response ing site (RRM, RNA recognition motif) and a to cold, is a major inducer of PGC-1α expres- domain rich in serine and arginine (RS, serine/ sion in brown adipose tissue and muscle via arginine-rich domain) [11, 12]. These two do- the cAMP signaling pathway and activation of mains are known to be involved in post-tran- protein kinase A (PKA) [10]. The expression of scriptional modifications of RNA [17]. Sequence PGC-1α is also increased in muscle after exer- 2+ analyses revealed that the PGC-1 family is con- cise, via activation of Ca /calmodulin-depen- served in many species, including primates, dent protein kinase IV (CaMKIV) and calcineu- rodents, ruminants, birds, amphibians and fish. rin A. Another mechanism known for regulating the expression of PGC-1α in muscles after exer- PGC-1 coactivators act as transcriptional regu- cise involves the p38 mitogen-activated protein lators but do not have a DNA-binding domain. kinase (p38 MAPK protein) and phosphoryla-

199 Am J Cancer Res 2019;9(2):198-211 PGC-1α and cancer

Table 1. Main transcription factors interacting with PGC-1α Transcription Factor Function, Role References NRF1/NRF2 Mitochondrial biogenesis [104, 105] PPARα/PPARβ Mitochondrial biogenesis; Fatty acid oxidation [106, 107] PPARγ Mitochondrial biogenesis; UCP1 expression [10, 57, 108-110] ERRα/ERRβ Mitochondrial biogenesis [111, 112] TRβ CPT1 expression [113, 114] FXR Triglyceride metabolism [115] LXRα/LXRβ Lipoprotein secretion [116, 117] GR; HNF4α; FOXO1 Neoglucogenesis [11, 12, 28, 118] Muscle fiber type1 gene regulation [59, 119] Erα/Erβ; PXR Unknown [11, 120] SREPB1/SREBP2 Lipogenesis; Lipoprotein secretion [116] Sox9 Chondrogenesis [121]

PGC-1α. In liver, the expres- sion of PGC-1α is increased in response to glucagon, a pan- creatic hormone that induc- es activation of cAMP and CREB [27]. This induction of PGC-1α in the liver during fasting leads to an increase in the expression of glucon- eogenesis genes that promo- tes the production of hepatic glucose and maintains glu- cose homeostasis [28] via the association of PGC-1α with transcription factors, such as Figure 2. PGC-1α, a co-activator implicated in several biological functions. HNF4α [29] or forkhead box PGC-1α is mainly regulated by three transcription factors protein O1 (FOXO1) [30]. (CREB, ATF2 and MEF2) that bind to the CREB-responsive element (CRE) and myocyte enhancer factor-2 (MEF2). The protein is also regulated by post- The transcriptional activity of translational modifications such as phosphorylation, deacetylation, acetyla- PGC-1α can also be modulat- tion and methylation. PGC-1α interacts with numerous transcription factors ed by post-translational mo- and is implicated in several biological functions. difications that positively or negatively affect its ability to tion of the myocyte enhancer factor-2 (MEF2) recruit complexes capable of remodeling chro- and activating-transcription factor 2 (ATF2) matin and activating gene transcription. These transcription factors [22-24]. post-translational modifications include phos- phorylation, acetylation, methylation and ubiq- PGC-1α is very sensitive to the energy status of uitination and are able to not only modulate the the cell. It is finely regulated by the AMP- intensity of the response mediated by PGC-1α, activated protein kinase (AMPK), a sensor of but also to determine which transcription factor cellular AMP levels. AMPK is activated in mus- will interact with PGC-1α. cle tissue during exercise and increases mito- chondrial biogenesis and metabolism. The PGC-1α is phosphorylated on serine and th- mitochondrial activation that is mediated by reonine residues at different sites by several AMPK requires PGC-1α activity [25, 26]. Si- kinases. The most well characterized of these milarly, fasting is another environmental sign- kinases are p38 AMPK [26, 31, 32], AKT [33], al that is known to regulate the expression of AMPK [34], S6 kinase (ribosomal protein S6

200 Am J Cancer Res 2019;9(2):198-211 PGC-1α and cancer

Figure 3. PGC-1α and cancer. Schematic summary of the different roles of PGC-1α in melanoma, breast, prostate and pancreatic cancer. The expression of PGC-1α is associated with modifications to cancer cell metabolism, differ- ent phenotypes associated with the aggressiveness of the cancer and patient survival. kinase) [35] and GSK3β (glycogen synthase pression of PGC-1α in adipocytes, muscle ce- kinase 3β) [36]. The phosphorylation of these lls, cardiac myocytes and osteoblasts leads to specific residues can lead to the activation of an increase in the amount of mitochondrial PGC-1α, as is observed for p38 MAPK and DNA [41-44]. PGC-1α initiates mitochondrial AMPK, which stabilize or activate PGC-1α, re- biogenesis by activating transcription factors spectively [26, 34]. In contrast, they can also that regulate the expression of mitochondrial induce the inhibition of PGC-1α, for example, proteins that are encoded by nuclear DNA [45]. Akt inhibits PGC-1α activity and GSK3β increas- Mitochondrial DNA encodes some protein sub- es the proteasomal degradation of PGC-1α units of the mitochondrial respiratory chain [36]. Finally, phosphorylation by S6 kinase pre- and proteins that are required for mitochondrial vents the interaction between PGC-1α and protein synthesis. All other mitochondrial pro- HNF4α (Figure 2) [35]. teins are encoded by nuclear DNA and there- fore, mitochondrial biogenesis requires coor- PGC-1α is also regulated by the action of de- dination between these two genomes. This co- acetylases and acetylases. For instance, sir- ordination is orchestrated by PGC-1α, which tuin 1 (SIRT1) activates PGC-1α by the deace- activates transcription factors that control the tylation of the lysine residues [37, 38] and expression of mitochondrial genes encoded by GCN5 (lysine acetyltransferase 2A) acetylates the nucleus [16, 46]. For example, PGC-1α acti- and inactivates PGC-1α [39]. PGC-1α is also vates NRF1 and NRF2 [44, 47-49], thus trigger- activated following the methylation of arginine ing the expression of several proteins: the residues in the C-terminal position by PRMT1 β-ATP synthase, cytochrome c, cytochrome c (protein arginine methyltransferase 1) [40]. oxidase subunits, transcription factor A mito- PGC-1α is a master regulator of oxidative chondrial (TFAM) [44, 50], and transcription metabolism factor B1 M and B2 M (TFB1M, TFB2M) [51]. Interestingly, NRFs induce TFAM, a transcrip- One of the main functions of PGC-1α is the tional activator, which translocates to the mito- control of energy metabolism, which is achiev- chondrion and plays an essential role in the ed by acting both on mitochondrial biogenes- replication, transcription, and maintenance of is and oxidative phosphorylation. This is con- mitochondrial DNA [52, 53]. By regulating the firmed by numerous in vitro and in vivo studies expression level of TFAM, PGC-1α controls the that have demonstrated that PGC-1α is involv- expression of proteins encoded by mitochon- ed in mitochondrial biogenesis. In fact, overex- drial DNA.

201 Am J Cancer Res 2019;9(2):198-211 PGC-1α and cancer

The induction of PGC-1α correlates with physi- tumors and cancer cells must therefore adapt ological situations such as cold, prolonged their metabolism, alternatively relying on gly- exercise or fasting (see above). In these circum- colysis or oxidative phosphorylation (OXPHOS). stances, fatty acids become the preferred These variations will modify the energy status energy substrate for the cells. Thus, PGC-1α of cancer cells and interfere with signaling controls expression of genes involved in fatty pathways (AMPK, mTORC1), transcription fac- acid oxidation [54] via PPARα [55]. PGC-1α tors (hypoxia-inducible factor 1 alpha HIF1α), induces expression of the fatty acid transport- protein expression (glucose transporter GLUT) ers CD36 and carnitine palmitoyltransferase I that are known to interact with PGC-1α. (CPT1), which allow fatty acids to enter into the cell (CD36) and then inside the mitochondria Secondly, cancer treatments such as radiation (CPT1), where they are ultimately oxidized. Two and chemotherapy have been shown to induce transcription factors have been identified as oxidative stress in tumors [66, 67]. ROS pro- partners of PGC-1α for the regulation of duction can either induce cell death or resis- β-oxidation: PPARα [18, 41, 56] and estrogen- tance to treatments through mechanisms im- related receptor alpha (ERRα) [57, 58]. plicating anti-oxidant [68]. Oxygen species are mainly produced by the mitochon- In addition to its roles in mitochondrial biogen- dria. Thus, regulation of mitochondrial biogen- esis and oxidative phosphorylation, PGC-1α is esis and PGC-1α may interfere with the res- also involved in the regulation of glucose me- ponses to treatments. tabolism. Induction of PGC-1α in skeletal mus- cle activates the expression of glucose trans- Finally, recent studies have shown that lipids porter 4 (GLUT4), via activation of the MEF2 are a source of energy for cancer cells. Adi- transcription factor, which increases glucose pocytes are important members of the tumor uptake in these cells [59]. This increase in microenvironment as they promote cancer cell intracellular glucose concentration is coupled aggressiveness through the release of cyto- with a decrease in glycolysis and an increase in kines (adipokines), such as Interleukin 6, to glycogen storage [60]. Indeed, the induction of increase the invasive properties of breast can- PGC-1α leads to the expression of PDK4, via cer cells, or chemokine (C-C motif) ligand 7, to ERRα. This inhibits glucose oxidation promote local dissemination of prostate cancer via inhibition of PDH and thus promotes gly- cells [4, 69]. Additionally, adipocytes release cogen synthesis [61, 62]. Any increase in oxi- fatty acids from lipid droplets, which are oxi- dation via the mitochondrial respiratory chain dized by fatty acid β-oxidation in cancer cells. is associated with the consequent production This metabolic crosstalk between adipocytes of ROS. Increased levels of ROS can lead to and cancer cells promotes aggressiveness and genotoxic stress and cell death. As a result, the formation of metastasis [70]. cells have developed defense mechanisms against these potentially toxic species. PGC-1α Role of PGC-1α in cancer is involved in the regulation of ROS levels by inducing the expression of several enzymes PGC-1α in melanoma involved in the detoxification of ROS, such as the superoxide dismutase (SOD), catalase and Recent studies have shown that melanoma is glutathione peroxidase (GPx) [63, 64]. The comprised of two subpopulations of cells, one ability of PGC-1α to induce these antioxidant expressing high levels of PGC-1α and a second enzymes are essential for the protection ag- subpopulation with very low PGC-1α expres- ainst ROS-induced cell damage and cell death sion [71-73]. These two populations have differ- [65]. ent metabolic and phenotypic profiles Figure ( 3). PGC-1α-overexpressing melanoma cells Why is PGC-1α suspected to play a role cancer have a very high rate of mitochondrial oxida- biology? tive metabolism and the ability to efficiently detoxify ROS, making them OXPHOS-depend- Cancer cells face numerous stresses and envi- ent and resistant to oxidative stress [73, 74]. ronmental conditions and PGC-1α may play a Overexpression of PGC-1α confers a significant role in their response to this environment. proliferative and survival potential, but PGC-1α Firstly, nutrient and oxygen supplies fluctuate in suppresses the invasive properties of these

202 Am J Cancer Res 2019;9(2):198-211 PGC-1α and cancer cells. Luo et al. have shown that PGC-1α sup- metabolic pathways, including glycolysis, glu- presses this pro-metastatic program through taminolysis, regulation of fatty acid oxidation the inhibitor of DNA binding 2 protein (ID2) and and detoxification [18, 80, 81]. Indeed, the the TCF4 transcription factor [74]. PGC-1α PGC-1α/ERRα complex modulates the expres- induces the transcription of ID2 that subse- sion of glutamine metabolism enzymes that quently binds to and inactivates the TCF4 tran- increase glutamine absorption and thus in- scription factor, preventing it from binding to crease Krebs cycle flux Figure( 3) [82]. In addi- the promoters of its target genes. Inactivation tion, the PGC-1α/ERRα axis co-stimulates ex- of TCF4 leads to reduced expression of genes pression of genes regulating lipogenesis [82]. related to the formation of metastases, includ- Thus, the intermediate metabolites, derived ing integrins, which are known to promote inva- from the catabolism of glutamine, are mainly sion and metastatic spread. In contrast, mela- directed towards the de novo biosynthesis of noma cells expressing low levels of PGC-1α fatty acids. Overexpression of PGC-1α, and contain few mitochondria, are highly dependent therefore the activation of ERRα, confers gr- on glycolysis and are highly sensitive to ROS- owth and proliferation advantages to breast induced apoptosis [73-75]. However, this sub- cancer cells, even when nutrients are scarce population of cells has a higher expression of and/or under conditions of hypoxia. These the pro-metastatic genes including integrins, observations correlate with clinical data show- transforming growth factor β (TGFβ) and Wnt. ing that overexpression of PGC-1α and its tar- The low expression of PGC-1α results in de- get glutaminolysis genes are associated with creased melanoma cell proliferation and str- poor prognosis for breast cancer patients. In engthened ability to form metastases. Once addition to its intrinsic effects on metabolism, implanted at the metastatic site, these cells PGC-1α is also involved in the regulation of are able to increase their expression of PGC- angiogenesis in mammary tumors [83]. It en- 1α, which increases growth [73, 74]. Expres- ables neovascularization and thus the increa- sion of PGC-1α in these two subpopulations se of available nutrients for mammary tumor of melanomas is regulated by the oncogenic cells, which leads to tumor growth. The mecha- transcription factor microphthalmia-associated nisms by which PGC-1α induces tumor angio- transcription factor (MITF) [73, 76, 77]. Given genesis have not yet been fully elucidated but the cytoprotective properties of PGC-1α, it is appear to be regulated by vascular endothelial not surprising that it is involved in the respon- growth factor (VEGF) independently of HIF-1 se to anticancer treatments. In melanoma, [83, 84]. Tumor cells must switch from a state induction of PGC-1α contributes to chemore- of rapid proliferation to an invasive phenotype sistance by increasing mitochondrial oxidative in order to be able to metastasize [85]. The metabolism [76]. In melanoma cells that st- pathways and metabolic requirements that rongly express PGC-1α, depletion of PGC-1α allow tumor cells to switch between prolifera- or inhibition of the respiratory chain increases tion and migration/invasion are still largely the efficacy of anti-melanoma chemotherapy unknown. Interestingly, a recent study suggest- by increasing the levels of ROS and apoptosis ed that PGC-1α may be involved in this mecha- [73, 76, 78, 79]. In conclusion, PGC-1α plays a nism [86]. This study showed that circulating dual role in melanoma by influencing both cell mammary tumor cells express high levels of survival and metastatic spread. PGC-1α and exhibit an increase in mitochon- drial biogenesis, resulting in the formation of PGC-1α in breast cancer metastases. In addition, the authors have shown that inhibition of PGC-1α in these cells In breast cancer, PGC-1α activates nuclear inhibits ATP production, reduces actin cytoskel- receptors and transcription factors, such as eton remodeling, decreases intravasation and PPARα, ERRα, NRF1 and NRF2, leading to inc- extravasation, and decreases cell survival [86]. reased mitochondrial biogenesis and OXPHOS Clinical analyzes also showed that PGC-1α lev- and thus generating the large amounts of ATP els are increased in mammary tumors of required for tumor growth. However, although patients with bone metastases, and revealed a mitochondrial respiration appears to be the negative correlation between PGC-1α expres- main biological function of PGC-1α, additional sion and patient survival [82, 86]. Although this crucial roles have also been described in other study does not identify the transcription fac-

203 Am J Cancer Res 2019;9(2):198-211 PGC-1α and cancer tor that is targeted by PGC-1α in circulating can- glycolysis, which is the consequence of the cer cells, these results show that PGC-1α is increase in the c-/PGC-1α ratio. Inhibition essential for the formation of metastases. The of c-MYC in this population of CSCs increases role of PGC-1α in bioenergetic flexibility and their sensitivity to metformin. These results thus mammary tumor cell metastasis was con- indicate that the balance between c-MYC and firmed by the study of Andrzejewskiet al., which PGC-1α determines the metabolic plasticity highlights the importance of PGC-1α in resis- and metformin sensitivity of pancreatic CSCs tance to treatments for this type of cancer [87]. [90]. Indeed, activation of several metabolic path- ways and detoxification of ROS by PGC-1α in PGC-1α in prostate cancer breast cancer tissue not only confers prolifera- tive advantages but it also leads to metabolic The contribution of PGC-1α to prostate cancer adaptations that can bypass therapies [88]. has only recently been considered and few For example, the use of ERRα antagonists pre- studies address this role [91-93]. The role of vents PGC-1α-mediated metabolic reprogram- PGC-1α in prostate cancer (PCa) is similar than ming and sensitizes mammary tumor cells to of melanoma, i.e., subpopulations with differ- therapies [88]. Another study shows that PGC- ent PGC-1α expression patterns: a sub-popula- 1α-mediated bioenergetic capabilities help tion overexpressing PGC-1α that is prolifera- mammary tumor cells to deal with the meta- tive but poorly invasive, and a sub-population bolic disruptor metformin [87]. In contrast, it with low expression of PGC-1α that is very has been shown that PGC-1α-overexpressing aggressive (Figure 3). Indeed, Shiota et al. sh- mammary tumor cells become dependent on ow that PGC-1α promotes tumor growth of a the folate cycle, which is essential for nucleo- subpopulation of androgen-dependent prostat- tide synthesis and tumor proliferation, thus ic cancer cells, via activation of the androgen these cells are more vulnerable to antifolates, receptor and its target genes [91]. Androgen such as methotrexate [89]. dependence is a primary characteristic of pros- tatic tumors and PGC-1α interacts with and PGC-1α in pancreatic cancer activates the (AR) to modify cancer cell metabolism, leading to an increase The c-MYC oncogene causes metabolic repro- in mitochondrial biogenesis and glucose and gramming, which is critical for the proliferation fatty acid oxidation [91]. In androgen-depen- and survival of tumor cells. Recently, it has dent PCa cells the inhibition of PGC-1α induces been shown in pancreatic adenocarcinoma cell cycle arrest in G1 phase and thus sup- that c-MYC is a direct regulator of PGC-1α [90]. presses their growth [91]. Moreover, in these Indeed, c-MYC binds to the promoter of PGC-1α cells, expression of PGC-1α is induced by AMPK and inhibits its transcription. Consequently, it in response to androgens [92]. This positive has been shown that the c-MYC/PGC-1α ratio regulation sustains expression of PGC-1α and dictates the metabolic phenotype of pancrea- increases its influence on tumor metabolism tic adenocarcinoma cells [90]. Pancreatic can- [92]. Recently, Torrano et al. identified PGC-1α cer stem cells (CSC) express high levels of PGC- as a suppressor of tumor progression based 1α because c-MYC is not expressed and the on a bioinformatic analysis of several PCa da- strong expression of PGC-1α is essential to tabases [93]. This observation was confirmed maintain mitochondrial respiration. Interest- in vivo using an androgen-independent pros- ingly, overexpression of PGC-1α makes CSCs tatic tumor cell line. In fact, injection of cells more sensitive to metformin than differentiat- overexpressing PGC-1α into a mouse model ed pancreatic tumor cells and they are unable decreased the progression and the formation to activate glycolysis in instances of metabolic of PCa metastases. This tumor suppressor stress because of the very low expression of effect of PGC-1α is mediated by ERRα and reg- c-MYC (Figure 3). In contrast, differentiated ulation of a catabolic transcriptional program. pancreatic tumor cells strongly express c-MYC Indeed, the PGC-1α/ERRα complex increases and have low levels of PGC-1α. Resistance of- with β-oxidation and Krebs cycle activity, which ten appears during treatment with metformin weakens the Warburg effect and therefore low- and an intermediate phenotype emerges in the ers tumor aggressiveness. In addition, this CSCs, with reduced OXPHOS but increased study shows that, in patients, expression of

204 Am J Cancer Res 2019;9(2):198-211 PGC-1α and cancer

PGC-1α gradually decreases with each increas- In conclusion, there is much evidence proving ing grade of tumor, thus highlighting the prog- that PGC-1α plays a role in cancer. However, it nostic value of PGC-1α in prostate cancer [93]. is important to elucidate its role in the initiation of tumorogenesis, the progression of tumors, PGC-1α in other cancers the formation of metastases and the response to treatments. Depending on the tissue, the The role of PGC-1α is emerging in other can- tumor stage, the microenvironment and cer- cers, including hepatocarcinoma [94], colon tainly the experimental conditions, tumor cells cancer [95-97], renal cell carcinoma [98] and show significant differences in the expression ovarian cancer [99]. In most of these studies, and the activity of PGC-1α. Unlike oncogenes or overexpression of the co-activator in cell lines tumor suppressor genes, mutations, amplifica- derived from these cancers inhibits prolifera- tions or deletions of PGC-1α are very rarely tion and/or its low expression is associated detected in tumors. Despite the fact that PGC- with a poor prognosis. However, paradoxically, 1α interacts with a wide variety of transcription chemotherapy has been shown to increase factors and is regulated by several signaling PGC-1α expression in colon cancer and pro- pathways, the exact mechanisms that drive the motes chemoresistance through the activation effects of PGC-1α are still poorly known and of sirtuin 1 and oxidative metabolism [100]. require further investigations.

Is PGC-1α a potential theragnosis tool? Acknowledgements

Depending on the type of cancer, the expres- We thank Nathalie Mazure, Stephan Clavel and sion level of PGC-1α has an impact on the prog- Nicolas Chevalier for carefully reading the man- nosis: high levels of expression predict a good uscript, and members of the “Targeting pros- outcome for patients with prostate cancer and tate cancer cell metabolism” Team for their melanoma, whereas it is bad for breast cancer support. This work was supported by a grant patients. In pancreatic cancer, PGC-1α is a from the Fondation ARC pour la recherche sur characteristic of cancer stem cells, which are le Cancer, l’Association pour la Recherche sur thought to be at the origin of cancer relapses. les Tumeurs de la Prostate (ARTP), ITMO-Can- Thus, level of expression of PGC-1α may be a cer. It has been supported by the French gov- valuable biomarker to diagnose the aggressive- ernment, through the UCAJEDI Investments in ness of cancers and, in some cases, the the Future project managed by the National response to treatment. The metabolic status of Research Agency (ANR) with the reference nu- cancer cells may affect the response to treat- mber ANR-15-IDEX-01. L.K. is supported by ments. For example, one can expect that cells the French Ministry of Research. F.B. and is a relying on oxidative phosphorylation would be CNRS investigator. more sensitive to drugs that target the mito- chondria. This hypothesis was raised by a Disclosure of conflict of interest recent study performed in non-small cell lung cancer showing that metformin does not affect None. cells that have been depleted of mitochondrial DNA [101]. Mitochondrial metabolism is funda- Address correspondence to: Frederic Bost, Uni- mental for the maintenance of cancer stems versité Nice Côte d’Azur, Inserm, C3M, Centre cells, and interestingly, several studies have Méditerranéen de Médecine Moléculaire (INSERM shown that cancer stem cells are very sensitive U1065), 151 Route de St Antoine de Ginestière, to metformin, which specifically targets mito- Nice 06200, France. E-mail: [email protected] chondrial metabolism [102, 103]. Furthermo- re, the status of PGC-1α could also be impor- References tant given its roles in drug detoxification and [1] Hanahan D and Weinberg RA. Hallmarks of the control of antioxidant enzyme expression. cancer: the next generation. Cell 2011; 144: Analysis of PGC-1α expression could therefo- 646-674. re provide important information concerning [2] Pavlova NN and Thompson CB. The emerging patient prognosis and in selecting which treat- hallmarks of cancer metabolism. Cell Metab ments to prescribe. 2016; 23: 27-47.

205 Am J Cancer Res 2019;9(2):198-211 PGC-1α and cancer

[3] Ben Sahra I, Laurent K, Loubat A, Giorgetti- vator 1 coactivators, energy homeostasis, and Peraldi S, Colosetti P, Auberger P, Tanti JF, Le metabolism. Endocr Rev 2006; 27: 728-735. Marchand-Brustel Y and Bost F. The antidia- [14] Andersson U and Scarpulla RC. Pgc-1-related betic drug metformin exerts an antitumoral ef- coactivator, a novel, serum-inducible coactiva- fect in vitro and in vivo through a decrease of tor of nuclear respiratory factor 1-dependent cyclin D1 level. Oncogene 2008; 27: 3576- transcription in mammalian cells. Mol Cell Biol 3586. 2001; 21: 3738-3749. [4] Dirat B, Ader I, Golzio M, Massa F, Mettouchi A, [15] Ydfors M, Fischer H, Mascher H, Blomstrand E, Laurent K, Larbret F, Malavaud B, Cormont M, Norrbom J and Gustafsson T. The truncated Lemichez E, Cuvillier O, Tanti JF and Bost F. In- splice variants, NT-PGC-1alpha and PGC-1al- hibition of the GTPase Rac1 mediates the anti- pha4, increase with both endurance and resis- migratory effects of metformin in prostate can- tance exercise in human skeletal muscle. cer cells. Mol Cancer Ther 2015; 14: 586-596. Physiol Rep 2013; 1: e00140. [5] Loubiere C, Clavel S, Gilleron J, Harisseh R, [16] Puigserver P and Spiegelman BM. Peroxisome Fauconnier J, Ben-Sahra I, Kaminski L, Laurent proliferator-activated receptor-gamma coacti- K, Herkenne S, Lacas-Gervais S, Ambrosetti D, vator 1 alpha (PGC-1 alpha): transcriptional Alcor D, Rocchi S, Cormont M, Michiels JF, Mari coactivator and metabolic regulator. Endocr B, Mazure NM, Scorrano L, Lacampagne A, Rev 2003; 24: 78-90. Gharib A, Tanti JF and Bost F. The energy dis- [17] Monsalve M, Wu Z, Adelmant G, Puigserver P, ruptor metformin targets mitochondrial integ- Fan M and Spiegelman BM. Direct coupling of rity via modification of calcium flux in cancer transcription and mRNA processing through cells. Sci Rep 2017; 7: 5040. the thermogenic coactivator PGC-1. Mol Cell [6] Zakikhani M, Dowling R, Fantus IG, Sonenberg 2000; 6: 307-316. N and Pollak M. Metformin is an AMP kinase- [18] Vega RB, Huss JM and Kelly DP. The coactiva- dependent growth inhibitor for breast cancer tor PGC-1 cooperates with peroxisome prolifer- cells. Cancer Res 2006; 66: 10269-10273. ator-activated receptor alpha in transcriptional [7] Cha JH, Yang WH, Xia W, Wei Y, Chan LC, Lim control of nuclear genes encoding mitochon- SO, Li CW, Kim T, Chang SS, Lee HH, Hsu JL, drial fatty acid oxidation enzymes. Mol Cell Biol Wang HL, Kuo CW, Chang WC, Hadad S, Purdie 2000; 20: 1868-1876. CA, McCoy AM, Cai S, Tu Y, Litton JK, Mittendorf [19] Tcherepanova I, Puigserver P, Norris JD, Spie- EA, Moulder SL, Symmans WF, Thompson AM, gelman BM and McDonnell DP. Modulation of Piwnica-Worms H, Chen CH, Khoo KH and -alpha transcriptional activity Hung MC. Metformin promotes antitumor im- by the coactivator PGC-1. J Biol Chem 2000; munity via endoplasmic-reticulum-associated 275: 16302-16308. degradation of PD-L1. Mol Cell 2018; 71: 606- [20] Delerive P, Wu Y, Burris TP, Chin WW and Suen 620, e607. CS. PGC-1 functions as a transcriptional co- [8] Shah MS and Brownlee M. Molecular and cel- activator for the retinoid X receptors. J Biol lular mechanisms of cardiovascular disorders Chem 2002; 277: 3913-3917. in diabetes. Circ Res 2016; 118: 1808-1829. [21] Knutti D, Kaul A and Kralli A. A tissue-specific [9] Besseiche A, Riveline JP, Gautier JF, Breant B coactivator of steroid receptors, identified in a and Blondeau B. Metabolic roles of PGC-1al- functional genetic screen. Mol Cell Biol 2000; pha and its implications for type 2 diabetes. 20: 2411-2422. Diabetes Metab 2015; 41: 347-357. [22] Akimoto T, Pohnert SC, Li P, Zhang M, Gumbs [10] Puigserver P, Wu Z, Park CW, Graves R, Wright C, Rosenberg PB, Williams RS and Yan Z. Exer- M and Spiegelman BM. A cold-inducible co- cise stimulates Pgc-1alpha transcription in activator of nuclear receptors linked to adap- skeletal muscle through activation of the p38 tive thermogenesis. Cell 1998; 92: 829-839. MAPK pathway. J Biol Chem 2005; 280: [11] Kressler D, Schreiber SN, Knutti D and Kralli A. 19587-19593. The PGC-1-related protein PERC is a selective [23] Knutti D and Kralli A. PGC-1, a versatile coacti- coactivator of . J Biol vator. Trends Endocrinol Metab 2001; 12: Chem 2002; 277: 13918-13925. 360-365. [12] Lin J, Puigserver P, Donovan J, Tarr P and Spie- [24] Zhao M, New L, Kravchenko VV, Kato Y, Gram gelman BM. Peroxisome proliferator-activated H, di Padova F, Olson EN, Ulevitch RJ and Han receptor gamma coactivator 1beta (PGC-1be- J. Regulation of the MEF2 family of transcrip- ta), a novel PGC-1-related transcription coacti- tion factors by p38. Mol Cell Biol 1999; 19: 21- vator associated with host cell factor. J Biol 30. Chem 2002; 277: 1645-1648. [25] Jørgensen SB, Wojtaszewski JF, Viollet B, An- [13] Handschin C and Spiegelman BM. Peroxisome dreelli F, Birk JB, Hellsten Y, Schjerling P, Vau- proliferator-activated receptor gamma coacti- lont S, Neufer PD, Richter EA and Pilegaard H.

206 Am J Cancer Res 2019;9(2):198-211 PGC-1α and cancer

Effects of alpha-AMPK knockout on exercise- [36] Olson BL, Hock MB, Ekholm-Reed S, Wohlschle- induced gene activation in mouse skeletal gel JA, Dev KK, Kralli A and Reed SI. SCFCdc4 muscle. FASEB J 2005; 19: 1146-1148. acts antagonistically to the PGC-1alpha tran- [26] Knutti D, Kressler D and Kralli A. Regulation of scriptional coactivator by targeting it for ubiqui- the transcriptional coactivator PGC-1 via tin-mediated proteolysis. Genes Dev 2008; 22: MAPK-sensitive interaction with a repressor. 252-264. Proc Natl Acad Sci U S A 2001; 98: 9713-9718. [37] Gerhart-Hines Z, Rodgers JT, Bare O, Lerin C, [27] Herzig S, Long F, Jhala US, Hedrick S, Quinn R, Kim SH, Mostoslavsky R, Alt FW, Wu Z and Bauer A, Rudolph D, Schutz G, Yoon C, Puig- Puigserver P. Metabolic control of muscle mito- server P, Spiegelman B and Montminy M. chondrial function and fatty acid oxidation CREB regulates hepatic gluconeogenesis through SIRT1/PGC-1alpha. EMBO J 2007; 26: through the coactivator PGC-1. Nature 2001; 1913-1923. 413: 179-183. [38] Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegel- [28] Yoon JC, Puigserver P, Chen G, Donovan J, Wu man BM and Puigserver P. Nutrient control of Z, Rhee J, Adelmant G, Stafford J, Kahn CR, glucose homeostasis through a complex of Granner DK, Newgard CB and Spiegelman BM. PGC-1alpha and SIRT1. Nature 2005; 434: Control of hepatic gluconeogenesis through 113-118. the transcriptional coactivator PGC-1. Nature [39] Lerin C, Rodgers JT, Kalume DE, Kim SH, Pan- 2001; 413: 131-138. dey A and Puigserver P. GCN5 acetyltransfer- [29] Rhee J, Inoue Y, Yoon JC, Puigserver P, Fan M, ase complex controls glucose metabolism Gonzalez FJ and Spiegelman BM. Regulation of through transcriptional repression of PGC-1al- hepatic fasting response by PPARgamma co- pha. Cell Metab 2006; 3: 429-438. activator-1alpha (PGC-1): requirement for he- [40] Teyssier C, Ma H, Emter R, Kralli A and Stallcup patocyte nuclear factor 4alpha in gluconeo- MR. Activation of coactivator genesis. Proc Natl Acad Sci U S A 2003; 100: PGC-1alpha by arginine methylation. Genes 4012-4017. Dev 2005; 19: 1466-1473. [30] Puigserver P, Rhee J, Donovan J, Walkey CJ, [41] Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Yoon JC, Oriente F, Kitamura Y, Altomonte J, Medeiros DM and Kelly DP. Peroxisome prolif- Dong H, Accili D and Spiegelman BM. Insulin- erator-activated receptor gamma coactivator-1 regulated hepatic gluconeogenesis through promotes cardiac mitochondrial biogenesis. J FOXO1-PGC-1alpha interaction. Nature 2003; Clin Invest 2000; 106: 847-856. 423: 550-555. [42] Russell LK, Mansfield CM, Lehman JJ, Kovacs [31] Fan M, Rhee J, St-Pierre J, Handschin C, Puig- A, Courtois M, Saffitz JE, Medeiros DM, Valen- server P, Lin J, Jäeger S, Erdjument-Bromage cik ML, McDonald JA and Kelly DP. Cardiac- H, Tempst P and Spiegelman BM. Suppression specific induction of the transcriptional coac- of mitochondrial respiration through recruit- tivator peroxisome proliferator-activated recep- ment of p160 binding protein to PGC-1al- tor gamma coactivator-1alpha promotes mito- pha: modulation by p38 MAPK. Genes Dev chondrial biogenesis and reversible cardiomy- 2004; 18: 278-289. opathy in a developmental stage-dependent [32] Puigserver P, Rhee J, Lin J, Wu Z, Yoon JC, manner. Circ Res 2004; 94: 525-533. Zhang CY, Krauss S, Mootha VK, Lowell BB and [43] Schreiber SN, Emter R, Hock MB, Knutti D, Spiegelman BM. Cytokine stimulation of ener- Cardenas J, Podvinec M, Oakeley EJ and Kralli gy expenditure through p38 MAP kinase acti- A. The estrogen-related receptor alpha (ERRal- vation of PPARgamma coactivator-1. Mol Cell pha) functions in PPARgamma coactivator 1al- 2001; 8: 971-982. pha (PGC-1alpha)-induced mitochondrial bio- [33] Li X, Monks B, Ge Q and Birnbaum MJ. Akt/ genesis. Proc Natl Acad Sci U S A 2004; 101: PKB regulates hepatic metabolism by directly 6472-6477. inhibiting PGC-1alpha transcription coactiva- [44] Wu Z, Puigserver P, Andersson U, Zhang C, tor. Nature 2007; 447: 1012-1016. Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, [34] Jäger S, Handschin C, St-Pierre J and Spiegel- Scarpulla RC and Spiegelman BM. Mecha- man BM. AMP-activated protein kinase (AMPK) nisms controlling mitochondrial biogenesis action in skeletal muscle via direct phosphory- and respiration through the thermogenic co- lation of PGC-1alpha. Proc Natl Acad Sci U S A activator PGC-1. Cell 1999; 98: 115-124. 2007; 104: 12017-12022. [45] Anderson R and Prolla T. PGC-1alpha in aging [35] Lustig Y, Ruas JL, Estall JL, Lo JC, Devarakonda and anti-aging interventions. Biochimica Et S, Laznik D, Choi JH, Ono H, Olsen JV and Spie- Biophysica Acta 2009; 1790: 1059-1066. gelman BM. Separation of the gluconeogenic [46] Kelly DP and Scarpulla RC. Transcriptional reg- and mitochondrial functions of PGC-1{alpha} ulatory circuits controlling mitochondrial bio- through S6 kinase. Genes Dev 2011; 25: genesis and function. Genes Dev 2004; 18: 1232-1244. 357-368.

207 Am J Cancer Res 2019;9(2):198-211 PGC-1α and cancer

[47] Scarpulla RC. Nuclear control of respiratory [59] Michael LF, Wu Z, Cheatham RB, Puigserver P, gene expression in mammalian cells. J Cell Adelmant G, Lehman JJ, Kelly DP and Spiegel- Biochem 2006; 97: 673-683. man BM. Restoration of insulin-sensitive glu- [48] Scarpulla RC. Nuclear control of respiratory cose transporter (GLUT4) gene expression in chain expression by nuclear respiratory factors muscle cells by the transcriptional coactivator and PGC-1-related coactivator. Ann N Y Acad PGC-1. Proc Natl Acad Sci U S A 2001; 98: Sci 2008; 1147: 321-334. 3820-3825. [49] Schreiber SN, Knutti D, Brogli K, Uhlmann T [60] Wende AR, Schaeffer PJ, Parker GJ, Zechner C, and Kralli A. The transcriptional coactivator Han DH, Chen MM, Hancock CR, Lehman JJ, PGC-1 regulates the expression and activity of Huss JM, McClain DA, Holloszy JO and Kelly DP. the orphan nuclear receptor estrogen-related A role for the transcriptional coactivator PGC- receptor alpha (ERRalpha). J Biol Chem 2003; 1alpha in muscle refueling. J Biol Chem 2007; 278: 9013-9018. 282: 36642-36651. [50] Rebelo AP, Dillon LM and Moraes CT. Mito- [61] Safdar A, Little JP, Stokl AJ, Hettinga BP, Akhtar chondrial DNA transcription regulation and M and Tarnopolsky MA. Exercise increases mi- nucleoid organization. J Inherit Metab Dis tochondrial PGC-1alpha content and promotes 2011; 34: 941-951. nuclear-mitochondrial cross-talk to coordinate [51] Scarpulla RC. Transcriptional paradigms in mitochondrial biogenesis. J Biol Chem 2011; mammalian mitochondrial biogenesis and 286: 10605-10617. function. Physiol Rev 2008; 88: 611-638. [62] Wende AR, Huss JM, Schaeffer PJ, Giguère V [52] Clayton DA. Transcription and replication of and Kelly DP. PGC-1alpha coactivates PDK4 animal mitochondrial DNAs. Int Rev Cytol gene expression via the orphan nuclear recep- 1992; 141: 217-232. tor ERRalpha: a mechanism for transcriptional [53] Parisi MA and Clayton DA. Similarity of human control of muscle glucose metabolism. Mol mitochondrial transcription factor 1 to high Cell Biol 2005; 25: 10684-10694. mobility group proteins. Science 1991; 252: [63] Chen SD, Yang DI, Lin TK, Shaw FZ, Liou CW 965-969. and Chuang YC. Roles of oxidative stress, [54] Leone TC, Lehman JJ, Finck BN, Schaeffer PJ, apoptosis, PGC-1α and mitochondrial biogen- Wende AR, Boudina S, Courtois M, Wozniak esis in cerebral ischemia. Int J Mol Sci 2011; DF, Sambandam N, Bernal-Mizrachi C, Chen Z, 12: 7199-7215. Holloszy JO, Medeiros DM, Schmidt RE, Saffitz [64] Valle I, Alvarez-Barrientos A, Arza E, Lamas S JE, Abel ED, Semenkovich CF and Kelly DP. and Monsalve M. PGC-1alpha regulates the PGC-1alpha deficiency causes multi-system mitochondrial antioxidant defense system in energy metabolic derangements: muscle dys- vascular endothelial cells. Cardiovasc Res function, abnormal weight control and hepatic 2005; 66: 562-573. steatosis. PLoS Biol 2005; 3: e101. [65] St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee [55] Dobrzyn P, Pyrkowska A, Jazurek M, Szymanski J, Jäger S, Handschin C, Zheng K, Lin J, Yang W, K, Langfort J and Dobrzyn A. Endurance train- Simon DK, Bachoo R and Spiegelman BM. ing-induced accumulation of muscle triglycer- Suppression of reactive oxygen species and ides is coupled to upregulation of stearoyl-CoA neurodegeneration by the PGC-1 transcription- desaturase 1. J Appl Physiol (1985) 2010; al coactivators. Cell 2006; 127: 397-408. 109: 1653-1661. [66] Leach JK, Van Tuyle G, Lin PS, Schmidt-Ullrich [56] Napal L, Marrero PF and Haro D. An intronic R and Mikkelsen RB. Ionizing radiation-in- peroxisome proliferator-activated receptor- duced, mitochondria-dependent generation of binding sequence mediates fatty acid induc- reactive oxygen/nitrogen. Cancer Res 2001; tion of the human carnitine palmitoyltransfer- 61: 3894-3901. ase 1A. J Mol Biol 2005; 354: 751-759. [67] Conklin KA. Chemotherapy-associated oxida- [57] Huss JM, Kopp RP and Kelly DP. Peroxisome tive stress: impact on chemotherapeutic effec- proliferator-activated receptor coactivator-1al- tiveness. Integr Cancer Ther 2004; 3: 294- pha (PGC-1alpha) coactivates the cardiac-en- 300. riched nuclear receptors estrogen-related re- [68] Liou GY and Storz P. Reactive oxygen species in ceptor-alpha and -gamma. Identification of cancer. Free Radic Res 2010; 44: 479-496. novel leucine-rich interaction motif within PGC- [69] Laurent V, Guerard A, Mazerolles C, Le Go- 1alpha. J Biol Chem 2002; 277: 40265-40274. nidec S, Toulet A, Nieto L, Zaidi F, Majed B, Ga- [58] Huss JM, Torra IP, Staels B, Giguère V and Kelly randeau D, Socrier Y, Golzio M, Cadoudal T, DP. Estrogen-related receptor alpha directs Chaoui K, Dray C, Monsarrat B, Schiltz O, Wang peroxisome proliferator-activated receptor al- YY, Couderc B, Valet P, Malavaud B and Muller pha signaling in the transcriptional control of C. Periprostatic adipocytes act as a driving energy metabolism in cardiac and skeletal force for prostate cancer progression in obesi- muscle. Mol Cell Biol 2004; 24: 9079-9091. ty. Nat Commun 2016; 7: 10230.

208 Am J Cancer Res 2019;9(2):198-211 PGC-1α and cancer

[70] Wang YY, Attane C, Milhas D, Dirat B, Dauvillier [79] Zhang G, Frederick DT, Wu L, Wei Z, Krepler C, S, Guerard A, Gilhodes J, Lazar I, Alet N, Lau- Srinivasan S, Chae YC, Xu X, Choi H, Dimwam- rent V, Le Gonidec S, Biard D, Herve C, Bost F, wa E, Ope O, Shannan B, Basu D, Zhang D, Ren GS, Bono F, Escourrou G, Prentki M, Nieto Guha M, Xiao M, Randell S, Sproesser K, Xu W, L, Valet P and Muller C. Mammary adipocytes Liu J, Karakousis GC, Schuchter LM, Gangad- stimulate breast cancer invasion through met- har TC, Amaravadi RK, Gu M, Xu C, Ghosh A, Xu abolic remodeling of tumor cells. JCI Insight W, Tian T, Zhang J, Zha S, Liu Q, Brafford P, 2017; 2: e87489. Weeraratna A, Davies MA, Wargo JA, Avadhani [71] Bogunovic D, O’Neill DW, Belitskaya-Levy I, NG, Lu Y, Mills GB, Altieri DC, Flaherty KT and Vacic V, Yu YL, Adams S, Darvishian F, Berman Herlyn M. Targeting mitochondrial biogenesis R, Shapiro R, Pavlick AC, Lonardi S, Zavadil J, to overcome drug resistance to MAPK inhibi- Osman I and Bhardwaj N. Immune profile and tors. J Clin Invest 2016; 126: 1834-1856. mitotic index of metastatic melanoma lesions [80] Chen H, McCaffery JM and Chan DC. Mitochon- enhance clinical staging in predicting patient drial fusion protects against neurodegenera- survival. Proc Natl Acad Sci U S A 2009; 106: tion in the cerebellum. Cell 2007; 130: 548- 20429-20434. 562. [72] Riker AI, Enkemann SA, Fodstad O, Liu S, Ren [81] Peters JM, Shah YM and Gonzalez FJ. The role S, Morris C, Xi Y, Howell P, Metge B, Samant of peroxisome proliferator-activated receptors RS, Shevde LA, Li W, Eschrich S, Daud A, Ju J in carcinogenesis and chemoprevention. Nat and Matta J. The gene expression profiles of Rev Cancer 2012; 12: 181-195. primary and metastatic melanoma yields a [82] McGuirk S, Gravel SP, Deblois G, Papadopoli transition point of tumor progression and me- DJ, Faubert B, Wegner A, Hiller K, Avizonis D, tastasis. BMC Med Genomics 2008; 1: 13. Akavia UD, Jones RG, Giguère V and St-Pierre J. [73] Vazquez F, Lim JH, Chim H, Bhalla K, Girnun G, PGC-1α supports glutamine metabolism in Pierce K, Clish CB, Granter SR, Widlund HR, breast cancer. Cancer Metab 2013; 1: 22. Spiegelman BM and Puigserver P. PGC1α ex- [83] Klimcakova E, Chénard V, McGuirk S, Germain pression defines a subset of human melano- D, Avizonis D, Muller WJ and St-Pierre J. PGC- ma tumors with increased mitochondrial ca- 1α promotes the growth of ErbB2/Neu-in- pacity and resistance to oxidative stress. duced mammary tumors by regulating nutrient Cancer Cell 2013; 23: 287-301. supply. Cancer Res 2012; 72: 1538-1546. [74] Luo C, Lim JH, Lee Y, Granter SR, Thomas A, [84] Arany Z, Foo SY, Ma Y, Ruas JL, Bommi-Reddy Vazquez F, Widlund HR and Puigserver P. A A, Girnun G, Cooper M, Laznik D, Chinsomboon PGC1α-mediated transcriptional axis sup- J, Rangwala SM, Baek KH, Rosenzweig A and presses melanoma metastasis. Nature 2016; Spiegelman BM. HIF-independent regulation 537: 422-426. of VEGF and angiogenesis by the transcription- [75] Piskounova E, Agathocleous M, Murphy MM, al coactivator PGC-1alpha. Nature 2008; 451: Hu Z, Huddlestun SE, Zhao Z, Leitch AM, John- 1008-1012. son TM, DeBerardinis RJ and Morrison SJ. Oxi- [85] Hoek KS, Eichhoff OM, Schlegel NC, Döbbeling dative stress inhibits distant metastasis by hu- U, Kobert N, Schaerer L, Hemmi S and Dum- man melanoma cells. Nature 2015; 527: mer R. In vivo switching of human melanoma 186-191. cells between proliferative and invasive states. [76] Haq R, Shoag J, Andreu-Perez P, Yokoyama S, Cancer Res 2008; 68: 650-656. Edelman H, Rowe GC, Frederick DT, Hurley AD, [86] LeBleu VS, O’Connell JT, Gonzalez Herrera KN, Nellore A, Kung AL, Wargo JA, Song JS, Fisher Wikman H, Pantel K, Haigis MC, de Carvalho DE, Arany Z and Widlund HR. Oncogenic BRAF FM, Damascena A, Domingos Chinen LT, Ro- regulates oxidative metabolism via PGC1α and cha RM, Asara JM and Kalluri R. PGC-1alpha MITF. Cancer Cell 2013; 23: 302-315. mediates mitochondrial biogenesis and oxida- [77] Ronai Z. The masters talk: the PGC-1α-MITF tive phosphorylation in cancer cells to promote axis as a melanoma energizer. Pigment Cell metastasis. Nat Cell Biol 2014; 16: 992-1003, Melanoma Res 2013; [Epub ahead of print]. 1001-1015. [78] Roesch A, Vultur A, Bogeski I, Wang H, Zimmer- [87] Andrzejewski S, Klimcakova E, Johnson RM, mann KM, Speicher D, Körbel C, Laschke MW, Tabaries S, Annis MG, McGuirk S, Northey JJ, Gimotty PA, Philipp SE, Krause E, Pätzold S, Vil- Chenard V, Sriram U, Papadopoli DJ, Siegel PM lanueva J, Krepler C, Fukunaga-Kalabis M, and St-Pierre J. PGC-1alpha promotes breast Hoth M, Bastian BC, Vogt T and Herlyn M. Over- cancer metastasis and confers bioenergetic coming intrinsic multidrug resistance in mela- flexibility against metabolic drugs. Cell Metab noma by blocking the mitochondrial respirato- 2017; 26: 778-787, e775. ry chain of slow-cycling JARID1B (high) cells. [88] Deblois G, Smith HW, Tam IS, Gravel SP, Caron Cancer Cell 2013; 23: 811-825. M, Savage P, Labbé DP, Bégin LR, Tremblay

209 Am J Cancer Res 2019;9(2):198-211 PGC-1α and cancer

ML, Park M, Bourque G, St-Pierre J, Muller WJ, [96] D’Errico I, Salvatore L, Murzilli S, Lo Sasso G, Giguère V. ERRα mediates metabolic adapta- Latorre D, Martelli N, Egorova AV, Polishuck R, tions driving lapatinib resistance in breast can- Madeyski-Bengtson K, Lelliott C, Vidal-Puig AJ, cer. Nat Commun 2016; 7: 12156. Seibel P, Villani G and Moschetta A. Peroxi- [89] Audet-Walsh É, Papadopoli DJ, Gravel SP, Yee some proliferator-activated receptor-gamma T, Bridon G, Caron M, Bourque G, Giguère V coactivator 1-alpha (PGC1alpha) is a metabol- and St-Pierre J. The PGC-1α/ERRα axis re- ic regulator of intestinal epithelial cell fate. presses one-carbon metabolism and promotes Proc Natl Acad Sci U S A 2011; 108: 6603- sensitivity to anti-folate therapy in breast can- 6608. cer. Cell Rep 2016; 14: 920-931. [97] Triki M, Lapierre M, Cavailles V and Mokdad- [90] Sancho P, Burgos-Ramos E, Tavera A, Bou Gargouri R. Expression and role of nuclear re- Kheir T, Jagust P, Schoenhals M, Barneda D, ceptor coregulators in colorectal cancer. World Sellers K, Campos-Olivas R, Grana O, Viera CR, J Gastroenterol 2017; 23: 4480-4490. Yuneva M, Sainz B Jr and Heeschen C. MYC/ [98] LaGory EL, Wu C, Taniguchi CM, Ding CC, Chi PGC-1alpha balance determines the metabolic JT, von Eyben R, Scott DA, Richardson AD and phenotype and plasticity of pancreatic cancer Giaccia AJ. Suppression of PGC-1α is critical stem cells. Cell Metab 2015; 22: 590-605. for reprogramming oxidative metabolism in re- [91] Shiota M, Yokomizo A, Tada Y, Inokuchi J, nal cell carcinoma. Cell Rep 2015; 12: 116- Tatsugami K, Kuroiwa K, Uchiumi T, Fujimoto 127. N, Seki N and Naito S. Peroxisome proliferator- [99] Zhang Y, Ba Y, Liu C, Sun G, Ding L, Gao S, Hao activated receptor gamma coactivator-1alpha J, Yu Z, Zhang J, Zen K, Tong Z, Xiang Y and interacts with the androgen receptor (AR) and Zhang CY. PGC-1alpha induces apoptosis in promotes prostate cancer cell growth by acti- human epithelial ovarian cancer cells through vating the AR. Mol Endocrinol 2010; 24: 114- a PPARgamma-dependent pathway. Cell Res 127. 2007; 17: 363-373. [92] Tennakoon JB, Shi Y, Han JJ, Tsouko E, White [100] Vellinga TT, Borovski T, de Boer VC, Fatrai S, MA, Burns AR, Zhang A, Xia X, Ilkayeva OR, Xin van Schelven S, Trumpi K, Verheem A, Snoeren L, Ittmann MM, Rick FG, Schally AV and Frigo N, Emmink BL, Koster J, Rinkes IH and Kranen- DE. Androgens regulate prostate cancer cell burg O. SIRT1/PGC1α-dependent increase in growth via an AMPK-PGC-1alpha-mediated oxidative phosphorylation supports chemo- metabolic switch. Oncogene 2014; 33: 5251- therapy resistance of colon cancer. Clin Cancer 5261. Res 2015; 21: 2870-2879. [93] Torrano V, Valcarcel-Jimenez L, Cortazar AR, [101] Cruz-Bermudez A, Vicente-Blanco RJ, Laza- Liu X, Urosevic J, Castillo-Martin M, Fernandez- Briviesca R, Garcia-Grande A, Laine-Menendez Ruiz S, Morciano G, Caro-Maldonado A, Guiu S, Gutierrez L, Calvo V, Romero A, Martin-Acos- M, Zuniga-Garcia P, Graupera M, Bellmunt A, ta P, Garcia JM and Provencio M. PGC-1alpha Pandya P, Lorente M, Martin-Martin N, David levels correlate with survival in patients with Sutherland J, Sanchez-Mosquera P, Bozal-Bas- stage III NSCLC and may define a new biomark- terra L, Zabala-Letona A, Arruabarrena-Aris- er to metabolism-targeted therapy. Sci Rep torena A, Berenguer A, Embade N, Ugalde-Ola- 2017; 7: 16661. no A, Lacasa-Viscasillas I, Loizaga-Iriarte A, [102] Hirsch HA, Iliopoulos D, Tsichlis PN and Struhl Unda-Urzaiz M, Schultz N, Aransay AM, Sanz- K. Metformin selectively targets cancer stem Moreno V, Barrio R, Velasco G, Pinton P, Cor- cells, and acts together with chemotherapy to don-Cardo C, Locasale JW, Gomis RR and block tumor growth and prolong remission. Carracedo A. The metabolic co-regulator PG- Cancer Res 2009; 69: 7507-7511. C1alpha suppresses prostate cancer metasta- [103] Hirsch HA, Iliopoulos D and Struhl K. Metfor- sis. Nat Cell Biol 2016; 18: 645-656. min inhibits the inflammatory response associ- [94] Liu R, Zhang H, Zhang Y, Li S, Wang X, Wang C, ated with cellular transformation and cancer Liu B, Zen K, Zhang CY, Zhang C and Ba Y. Per- stem cell growth. Proc Natl Acad Sci U S A oxisome proliferator-activated receptor gam- 2013; 110: 972-977. ma coactivator-1 alpha acts as a tumor sup- [104] Mootha VK, Lindgren CM, Eriksson KF, Subra- pressor in hepatocellular carcinoma. Tumour manian A, Sihag S, Lehar J, Puigserver P, Carls- Biol 2017; 39: 1010428317695031. son E, Ridderstrale M, Laurila E, Houstis N, [95] De Souza-Teixeira F, Alonso-Molero J, Ayán C, Daly MJ, Patterson N, Mesirov JP, Golub TR, Vilorio-Marques L, Molina AJ, González-Don- Tamayo P, Spiegelman B, Lander ES, quiles C, Davila-Batista V, Fernández-Villa T, de Hirschhorn JN, Altshuler D and Groop LC. PGC- Paz JA and Martín V. PGC-1α as a biomarker of 1alpha-responsive genes involved in oxidative physical activity-protective effect on colorectal phosphorylation are coordinately downregu- cancer. Cancer Prev Res (Phila) 2018; 11: lated in human diabetes. Nat Genet 2003; 34: 523-534. 267-273.

210 Am J Cancer Res 2019;9(2):198-211 PGC-1α and cancer

[105] Wu Z, Puigserver P, Andersson U, Zhang C, [114] Zhang Y, Ma K, Song S, Elam MB, Cook GA and Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Park EA. Peroxisomal proliferator-activated re- Scarpulla RC and Spiegelman BM. Mecha- ceptor-gamma coactivator-1 alpha (PGC-1 al- nisms controlling mitochondrial biogenesis pha) enhances the thyroid hormone induction and respiration through the thermogenic co- of carnitine palmitoyltransferase I (CPT-I al- activator PGC-1. Cell 1999; 98: 115-124. pha). J Biol Chem 2004; 279: 53963-53971. [106] Vega RB, Huss JM and Kelly DP. The coactiva- [115] Zhang Y, Castellani LW, Sinal CJ, Gonzalez FJ tor PGC-1 cooperates with peroxisome prolifer- and Edwards PA. Peroxisome proliferator-acti- ator-activated receptor alpha in transcriptional vated receptor-gamma coactivator 1alpha control of nuclear genes encoding mitochon- (PGC-1alpha) regulates triglyceride metabo- drial fatty acid oxidation enzymes. Mol Cell Biol lism by activation of the nuclear receptor FXR. 2000; 20: 1868-1876. Genes Dev 2004; 18: 157-169. [107] Wang YX, Lee CH, Tiep S, Yu RT, Ham J, Kang H [116] Lin J, Yang R, Tarr PT, Wu PH, Handschin C, Li and Evans RM. Peroxisome-proliferator-activat- S, Yang W, Pei L, Uldry M, Tontonoz P, Newgard ed receptor delta activates fat metabolism to CB and Spiegelman BM. Hyperlipidemic ef- prevent obesity. Cell 2003; 113: 159-170. fects of dietary saturated fats mediated [108] Guan HP, Ishizuka T, Chui PC, Lehrke M and through PGC-1beta coactivation of SREBP. Cell Lazar MA. Corepressors selectively control the 2005; 120: 261-273. transcriptional activity of PPARgamma in adi- [117] Oberkofler H, Schraml E, Krempler F and pocytes. Genes Dev 2005; 19: 453-461. Patsch W. Potentiation of tran- [109] Huss JM and Kelly DP. Nuclear receptor signal- scriptional activity by peroxisome-proliferator- ing and cardiac energetics. Circ Res 2004; 95: activated receptor gamma co-activator 1 al- 568-578. pha. Biochem J 2003; 371: 89-96. [110] Kamei Y, Ohizumi H, Fujitani Y, Nemoto T, Tana- [118] Mortensen OH, Frandsen L, Schjerling P, ka T, Takahashi N, Kawada T, Miyoshi M, Ezaki Nishimura E and Grunnet N. PGC-1alpha and O and Kakizuka A. PPARgamma coactivator PGC-1beta have both similar and distinct ef- 1beta/ERR ligand 1 is an ERR protein ligand, fects on myofiber switching toward an oxidative whose expression induces a high-energy ex- phenotype. Am J Physiol Endocrinol Metab penditure and antagonizes obesity. Proc Natl 2006; 291: E807-816. Acad Sci U S A 2003; 100: 12378-12383. [119] Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O, [111] Mootha VK, Handschin C, Arlow D, Xie X, St Michael LF, Puigserver P, Isotani E, Olson EN, Pierre J, Sihag S, Yang W, Altshuler D, Puigserv- Lowell BB, Bassel-Duby R and Spiegelman BM. er P, Patterson N, Willy PJ, Schulman IG, Hey- Transcriptional co-activator PGC-1 alpha drives man RA, Lander ES and Spiegelman BM. Er- the formation of slow-twitch muscle fibres. Na- ralpha and Gabpa/b specify PGC-1alpha- ture 2002; 418: 797-801. dependent oxidative phosphorylation gene ex- [120] Bhalla S, Ozalp C, Fang S, Xiang L and Kemper pression that is altered in diabetic muscle. JK. Ligand-activated inter- Proc Natl Acad Sci U S A 2004; 101: 6570- feres with HNF-4 signaling by targeting a com- 6575. mon coactivator PGC-1alpha. Functional impli- [112] Schreiber SN, Emter R, Hock MB, Knutti D, cations in hepatic cholesterol and glucose Cardenas J, Podvinec M, Oakeley EJ and Kralli metabolism. J Biol Chem 2004; 279: 45139- A. The estrogen-related receptor alpha (ERRal- 45147. pha) functions in PPARgamma coactivator 1al- [121] Kawakami Y, Tsuda M, Takahashi S, Taniguchi pha (PGC-1alpha)-induced mitochondrial bio- N, Esteban CR, Zemmyo M, Furumatsu T, Lotz genesis. Proc Natl Acad Sci U S A 2004; 101: M, Izpisúa Belmonte JC and Asahara H. Tran- 6472-6477. scriptional coactivator PGC-1alpha regulates [113] Wu Y, Delerive P, Chin WW and Burris TP. Re- chondrogenesis via association with Sox9. quirement of helix 1 and the AF-2 domain of Proc Natl Acad Sci U S A 2005; 102: 2414- the thyroid for coactivation 2419. by PGC-1. J Biol Chem 2002; 277: 8898-8905.

211 Am J Cancer Res 2019;9(2):198-211