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Mitochondrial Reprogramming in Tumor Progression and Therapy M Published OnlineFirst December 9, 2015; DOI: 10.1158/1078-0432.CCR-15-0460 Molecular Pathways Clinical Cancer Research Molecular Pathways: Mitochondrial Reprogramming in Tumor Progression and Therapy M. Cecilia Caino and Dario C. Altieri Abstract Small-molecule inhibitors of the phosphoinositide 3-kinase mitochondrial Hsp90s in preclinical development (gamitrinib) (PI3K), Akt, and mTOR pathway currently in the clinic produce a prevents adaptive mitochondrial reprogramming and shows paradoxical reactivation of the pathway they are intended to potent antitumor activity in vitro and in vivo. Other therapeutic suppress. Furthermore, fresh experimental evidence with PI3K strategies to target mitochondria for cancer therapy include antagonists in melanoma, glioblastoma, and prostate cancer small-molecule inhibitors of mutant isocitrate dehydrogenase shows that mitochondrial metabolism drives an elaborate process (IDH) IDH1 (AG-120) and IDH2 (AG-221), which opened new of tumor adaptation culminating with drug resistance and met- therapeutic prospects for patients with high-risk acute myelog- astatic competency. This is centered on reprogramming of mito- enous leukemia (AML). A second approach of mitochondrial chondrial functions to promote improved cell survival and to fuel therapeutics focuses on agents that elevate toxic ROS levels from the machinery of cell motility and invasion. Key players in these a leaky electron transport chain; nevertheless, the clinical expe- responses are molecular chaperones of the Hsp90 family com- rience with these compounds, including a quinone derivative, partmentalized in mitochondria, which suppress apoptosis via ARQ 501, and a copper chelator, elesclomol (STA-4783) is phosphorylation of the pore component, Cyclophilin D, and limited. In light of this evidence, we discuss how best to target enable the subcellular repositioning of active mitochondria to a resurgence of mitochondrial bioenergetics for cancer therapy. membrane protrusions implicated in cell motility. An inhibitor of Clin Cancer Res; 22(3); 540–5. Ó2015 AACR. Background state (5), inactivation of tumor suppressors, for instance p53 (6), or activating mutations in the Ras oncogene (7) stimulates gly- Rewiring of mitochondrial function in tumors colysis at the expense of oxidative phosphorylation, and stabili- Unlike normal cells that oxidize pyruvate in the mitochondrial zation of HIF1, a master regulator of oxygen homeostasis, dam- respiratory chain to produce bioenergy (ATP), tumors rely on a pens mitochondrial respiration to promote glycolysis (8). Irre- "fermentative", glycolytic metabolism that converts glucose to spective, a rewired tumor metabolism is clearly important for pyruvate and then lactate in the cytosol, irrespective of oxygen disease outcome, conferring aggressive traits of metastatic com- availability (1). Recognized almost a century ago, this "Warburg petency and drug resistance (4). Not surprisingly. based on these effect" is now considered a hallmark of cancer (2), independent of findings, mitochondrial function has been dubbed as a "tumor stage or genetic makeup. Why tumors with their high biosynthetic suppressor" (9), restoring oxidative phosphorylation was pro- needs rely on an energetically inefficient metabolism is not posed as a therapeutic target (10), and agents that inhibit glycol- entirely clear. However, the role of glycolysis in generation of ysis have entered clinical testing in cancer patients (see below). biomass to support cell proliferation (1), dampening the pro- On the other hand, the dichotomy between glycolysis and duction of toxic ROS from mitochondria (3), and adaptation to a oxidative phosphorylation in cancer bioenergetics may not be as hypoxic microenvironment (4), have all been implicated as rigid as previously thought. In fact, we know that mitochondria drivers of metabolic rewiring. remain fully functional in most tumors (11), oxidative phosphor- This compounds additional evidence that, at least in certain ylation still accounts for a large fraction of ATP produced in cancer tumors, disabling mitochondrial respiration favors disease (12), and even under conditions of severe hypoxia, cytochromes progression. Accordingly, loss-of-function mutations in oxidative are fully oxidized to support cellular respiration (13). This bio- phosphorylation genes produce a pro-oncogenic, pseudo-hypoxic chemical evidence fits well with a flurry of functional data that point to oxidative phosphorylation as an important cancer driver (Table 1). Accordingly, mitochondrial respiration contributes to Prostate Cancer Discovery and Development Program, Tumor Micro- oncogene-dependent transformation (14) and metabolic repro- environment and Metastasis Program, The Wistar Institute, Philadel- gramming (15), supports energy-intensive mechanisms of protein phia, Pennsylvania. translation in tumors (16), maintains cancer "stemness" (17), Corresponding Author: Dario C. Altieri, The Wistar Institute Cancer Center, 3601 favors malignant repopulation after oncogene ablation (18), and Spruce Street, Philadelphia, PA 19104. Phone: 215-495-6970; Fax: 215-495-2638; promotes the emergence of drug resistance (ref. 19; Table 1 E-mail: [email protected] summarizes the mitochondrial pathways involved in cancer and doi: 10.1158/1078-0432.CCR-15-0460 the effect of targeting such pathways). In addition, there is evidence Ó2015 American Association for Cancer Research. that oxidative phosphorylation may be required to support tumor 540 Clin Cancer Res; 22(3) February 1, 2016 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst December 9, 2015; DOI: 10.1158/1078-0432.CCR-15-0460 Mitochondrial Control of Tumor Progression Table 1. Mitochondrial pathways that contribute to cancer Function Genes/pathway Targeted by Effect on tumors Cancer type Ref. Apoptosis resistance PDK-dependent metabolic- DCA (PDK inhibitor) #Xenograft growth by 50%– Various 10 electrical remodeling involves 85% vs. vehicle NFAT, mitochondria ROS and Kþ channels Kv1.5 Oncogene–dependent Kras V12, glutamine metabolism LSL-Kras G12D x TFAMfl/fl #Tumor load by 70%–80% Lung 14 transformation (ALT2, GLS) pentose vs. Kras alone phosphate pathway (GPI), CIII (Rieske) ROS/ERK Metabolic reprogramming c-Myc, miR-23a/b, 15 mitochondrial glutaminase (GLS), glutamine catabolism and transport (ASCT2), TCA cycle Protein translation mTORC1/4E-BPs translation of 16 mt-mRNAs (including the components of complex V, mt ribosomal proteins and TFAM) Cancer stemness IMP2, OxPhos (NDUFS3, IMP2 shRNA "Survival of mice injected Glioblastoma 17 NDUFS7, NDUF3) with gliomaspheres by 60%–160% (IMP2 sh vs. control sh) Malignant repopulation Kras, p53, mitochondrial Oligomycin (ETC inhibitor) "Maximal survival of mice Pancreatic ductal 18 OxPhos, b-oxidation, bearing regressed tumors adenocarcinoma biogenesis (PGC-1a) by >300% Drug resistance H3K4-demethylase JARID1B, Vemurafenib (V600E Braf #Xenograft growth by 50%– Melanoma 19 mitochondrial OxPhos inhibitor) þ phenformin 60% vs. single (biguanide hypoglycemic vemurafenib agent) Drug resistance mtHsp90, Akt2 translocation to BEZ235 (PI3K antagonist) " Median survival of mice Glioblastoma 35 mitochondria, CypD þ gamitrinib (mtHsp90 bearing GBM by >40% vs. inhibitor) monotherapy Tumor cell motility mtHsp90, AMPK, mTOR, ULK1/ mtHsp90 siRNA #Breast cancer metastasis to Various 20 FIP200/FAK bone by 80% Constitutive active mutant #Lung cancer metastasis to of AMPK or ULK1 liver by 60%–80% expression Metastasis PGC-1a, mitochondrial PGC-1a shRNA #Breast cancer metastasis to Various 21 biogenesis, OxPhos lung by 70%–90% NOTE: The main mitochondrial functions implicated in cancer are presented along the molecular pathways involved. Where available, the effect of targeting these mitochondrial pathways in tumorigenesis, tumor growth, or metastasis are presented. Abbreviations: 4E-BPs, eukaryotic translation initiation factor 4E binding proteins; ALT2, mitochondrial alanine aminotransferase; CIII, electron transport chain complex III; GBM, glioblastoma; GLS, glutaminase; GPI, glucose 6-phosphate isomerase; IMP2, insulin-like growth factor 2 mRNA-binding protein 2; PDK, pyruvate dehydrogenase kinase; mTORC1, mammalian target of rapamacyn complex 1; NDUFS3/7, NADH dehydrogenase (ubiquinone) iron-sulfur protein 3 and 7; NDUF3, NADH dehydrogenase (ubiquinone) 1a complex assembly factor 3; NFAT, nuclear factor of activated T cells; OxPhos, oxidative phosphorylation; PGC-1a, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; ROS, reactive oxygen species; TCA, tricarboxylic acid. cell motility (20) and metastasis (21), potentially under conditions compensatory response promotes survival and maintains a pro- of stress or limited nutrient availability. Mechanistic aspects of how liferative advantage in genetically disparate tumors, correlating tumors may regulate oxidative phosphorylation have also come with worse outcome in lung cancer patients. Several groups have into better focus, pointing to a key role of protein folding quality recently demonstrated the importance of OxPhos and protein control maintained by mitochondria-localized Hsp90 chaperones folding in the mitochondria for metastatic dissemination in mouse (22), as well as organelle proteases (23), in mitochondrial homeo- models. For instance, targeting OxPhos by siRNA knockdown of stasis in tumors. In this context, Hsp90 chaperones predominantly mtHsp90 led to 80% reduction in breast cancer metastasis
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