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P53: Protection Against Tumor Growth Beyond Effects on Cell Cycle and Apoptosis Xuyi Wang1,2, Evan R

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P53: Protection Against Tumor Growth Beyond Effects on Cell Cycle and Apoptosis Xuyi Wang1,2, Evan R Published OnlineFirst November 16, 2015; DOI: 10.1158/0008-5472.CAN-15-0563 Cancer Review Research p53: Protection against Tumor Growth beyond Effects on Cell Cycle and Apoptosis Xuyi Wang1,2, Evan R. Simpson1,3, and Kristy A. Brown1,2 The tumor suppressor p53 has established functions in cancer. lication by Wang and colleagues demonstrates for the first time Specifically, it has been shown to cause cell-cycle arrest and that p53 is a key negative regulator of aromatase and, hence, apoptosis in response to DNA damage. It is also one of the most estrogen production in the breast tumor microenvironment. It commonly mutated or silenced genes in cancer and for this reason goes further by demonstrating that an important regulator of has been extensively studied. Recently, the role of p53 has been aromatase, the obesity-associated and tumor-derived factor pros- shown to go beyond its effects on cell cycle and apoptosis, with taglandin E2, inhibits p53 in the breast adipose stroma. This effects on metabolism emerging as a key contributor to cancer review presents these findings in the context of established and growth in situations where p53 is lost. Beyond this, the role of p53 emerging roles of p53 and discusses possible implications for the in the tumor microenvironment is poorly understood. The pub- treatment of breast cancer. Cancer Res; 75(23); 5001–7. Ó2015 AACR. Background induces apoptosis. The mitochondrial pathway is mainly reg- ulated by p53 effector Bcl-2 proteins such as Bax (4) and PUMA Traditional tumor suppressor functions of p53 (5). In tumors with wild-type p53, p53 responses can be The tumor suppressor p53, encoded by the TP53 gene, is the inhibited by downregulating p53 activity or its effectors' activ- most commonly silenced or mutated gene in cancer, with 50% to þ ity. For instance, in estrogen receptor–positive (ER )breast 55% of human cancers having experienced the loss of wild-type cancers, ER prevents the p53-mediated apoptotic response by p53 activity (reviewed in ref. 1). Under normal conditions, p53 directly interacting with p53 (6). levels are low and, in some cases, undetectable. However, stress Although most p53 mutations result in inactivation or dys- signals such as DNA damage, oncogene activation, and hypoxia function of p53, some mutations in p53 lead to the selective loss stabilize p53 protein and induce increased cellular p53 levels by of apoptotic functions while retaining the ability to induce cell- posttranslational modifications such as phosphorylation and cycle arrest. Certain p53 mutations lead to p53 becoming onco- acetylation. Activated p53 causes a variety of responses including genic through gain-of-function mechanisms (7). Cell-cycle arrest cell-cycle arrest or apoptosis, thereby providing a critical barrier driven by p53 requires the transcription of p21, which is a cyclin- against tumor development (reviewed in refs. 1, 2). As a tran- dependent kinase inhibitor, or other p53 target genes such as scription factor, activated p53 binds to a number of genes that 14–3–3s and GADD45 (8). In general, DNA damage or stress will contain p53-binding sites within their regulatory regions. Bioin- increase levels of p53 protein, which in turn induces p21 tran- formatic studies have found more than 4,000 putative p53- scription and leads to cell-cycle arrest at G , allowing cells to binding sites in the existing human genome. Somatic mutations 1 survive until the damage has been repaired or the stress removed in TP53 are common in cancers and are associated with poor (9, 10). The G arrest is primarily regulated by p21, whereas G prognosis and low response to chemotherapy (3). 1 2 arrest is stimulated by GADD45, p21, and 14–3–3s (11). The role Numerous p53 target genes have been identified as down- of p53 to suppress tumor growth and promote apoptosis via these stream effectors of p53 with changesincellfunctionbeing pathways is well-characterized. However, novel roles for p53 are dependent on the regulation of several genes (2). For example, emerging and these are proving important contributors to the p53 mediates cell apoptosis by activating mitochondrial and tumor suppressor functions of p53. death receptor–induced apoptotic pathways, both pathways resulting in the induction of caspase signaling, which then p53 as a metabolic checkpoint Emerging evidence suggests that p53 is also involved in the regulation of metabolism and cell homeostasis without causing 1 Metabolism and Cancer Laboratory, Centres for Cancer Research and cell-cycle arrest or apoptosis (12). For example, nutrient deficien- Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Victoria, Australia. 2Department of Physiology, Monash Uni- cy leads to the activation of p53 through direct phosphorylation at versity, Clayton, Victoria, Australia. 3Department of Biochemistry and Ser15 by AMP-activated protein kinase (AMPK), a key regulator of Molecular Biology, Monash University, Clayton, Victoria, Australia. cell metabolism (13). p53 also regulates metabolism and cell Corresponding Author: Kristy A. Brown, Metabolism and Cancer Laboratory, homeostasis in normal cells and tissues. Lipin1 is a recently Hudson Institute of Medical Research, 27–31 Wright Street, Clayton, Victoria identified p53 target gene that regulates the expression of genes 3168, Australia. Phone: 61-3-95944333; Fax: 61-3-95946125; E-mail: involved in fatty acid oxidation through PPARa (14). Under [email protected] nutrient/glucose deprivation conditions, p53 is upregulated by doi: 10.1158/0008-5472.CAN-15-0563 AMPK and stimulates Lipin1 and malonyl-CoA decarboxylase Ó2015 American Association for Cancer Research. expression, leading to an increase in fatty acid oxidation (14, 15). www.aacrjournals.org 5001 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst November 16, 2015; DOI: 10.1158/0008-5472.CAN-15-0563 Wang et al. This allows cells to use fatty acids as an alternative energy source. presence of FSK/PMA (30). This, in turn, drives the expression Reciprocally, p53 also promotes the expression of AMPK, leading of aromatase. We have also recently demonstrated that HIF1a to the negative regulation of mTOR (16). The PI3K/Akt/mTOR with known roles in promoting tumor growth and emerging pathway can suppress apoptosis and stimulate proinflammatory roles in regulating metabolism is stimulated by PGE2 in ASCs gene expression, which in turn promotes cancer growth and and stimulates the expression of aromatase. Unpublished data progression (17). Negative regulation of mTOR is also observed from Sasano and colleagues showed enhanced aromatase in autophagy, which can be induced by starvation and metabolic expression and staining in tightly packed undifferentiated ASCs stresses. around tumor cells in patients with breast cancer. This process Oncogenic transformation is often associated with enhanced of undifferentiation and increased stromal cell proliferation is aerobic glycolysis and reduced oxidative phosphorylation, which known as desmoplasia, which leads to the formation of a dense is known as the Warburg effect. Aerobic glycolysis allows cancer fibroblast layer surrounding malignant epithelial cells; it is cells to generate ATP as well as stimulate anaplerotic metabolism essential for structural and biochemical support of tumor of intermediates such as a-ketoglutarate to support cancer cell growth (31, 32). proliferation and survival (18). Recently, p53 has been shown to inhibit the Warburg effect by reducing glycolysis and enhancing Li–Fraumeni syndrome oxidative phosphorylation via upregulation of genes including Li–Fraumeni syndrome (LFS) is a rare autosomal dominant TIGAR and SCO2 (synthesis of cytochrome oxidase 2), as well as hereditary syndrome with the majority of affected individuals inhibiting the expression of glucose transporters GLUT1, GLUT3, carrying germ line mutations in the TP53 gene (33). LFS is and GLUT4 (19, 20). SCO2 increases mitochondrial respiration characterized by a high susceptibility of developing a number of and TIGAR inhibits glycolysis and promotes NADPH production malignancies, predominantly in childhood and early adult life. and glutathione recycling, whereas repression of glucose trans- Half of individuals with LFS develop at least one LFS-associated porters blocks the uptake of glucose (19). cancer by age 30 and 15% to 35% of cancer survivors with LFS will In summary, a number of genes are regulated by p53 to develop multiple primary tumors over their lifetimes (34). It has maintain metabolism and energy homeostasis in cells/tissues also been proposed that patients with LFS have deregulated under normal and stressed physiologic conditions. Changes in metabolism, including increased oxidative stress and hypoxia, to tumor cell metabolism are now recognized as a hallmark of cancer provide a microenvironment conducive to tumor formation, (21) and p53 is integral to this process. which can be one complication of dysfunctional p53 for these patients (35). Breast cancer is the most common type of cancer in Dysregulated metabolism as a driver of estrogen production in þ women with LFS and the majority of tumors are ER (36). the breast adipose Moll and colleagues previously found that wild-type p53 can Adipose tissue is responsible for energy storage and acts as an accumulate in the cytoplasm of tumor cells in inflammatory endocrine organ that regulates metabolism via endocrine, breast cancers, leading to functional inactivation
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