Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Review Article

The Role of PGC-1α in Digestive System Malignant Tumours

Author(s): Qiushuang Zhang, Wei Chen, Chao Xie, Xiaoshuo Dai, Junfen Ma and Jing Lu*

Volume 20, Issue 3, 2020

Page: [276 - 285] Pages: 10

DOI: 10.2174/1871520619666191105125409

Price: $65


Background: Cancer is increasingly becoming the leading cause of death in many countries, and malignant tumours of the digestive system account for majority of cancer incidence and mortality cases. Metabolism has been identified as a core hallmark of cancer. Peroxisome proliferator activated receptor gamma coactivator-1 alpha (PGC-1α) is a pivotal regulator of mitochondrial energy metabolism. Accumulating evidence reveals that PGC-1α is essential in cancer development.

Objective: We summarize the latest research progress of PGC-1α in common digestive system malignant tumours. Some related modulators and pathways are analyzed as well.

Methods: We conducted a literature review on the development of PGC-1α in common digestive system malignant tumours.

Results: In colorectal cancer, PGC-1α appears to provide growth advantages by different pathways, although it has also been reported to have opposite effects. The previous studies of PGC-1α on liver cancer also demonstrated different effects by sundry pathways. Concerning gastric cancer, PGC-1α promotes cell proliferation, apoptosis in vitro and tumour growth in vivo. AMPK/SIRT1/PGC-1α is related to the inhibition of apoptosis in pancreatic cancer cells. Pancreatic cancer stem cells are strongly dependent on mitochondrial oxidative phosphorylation. PGC-1α is required to maintain the stemness property of pancreatic cancer stem cells.

Conclusion: We explore diverse mechanisms that explain the dichotomous functions of PGC-1α on tumorigenesis, and discuss the latest research concerning digestive system malignant tumours. This review would provide better comprehension of the field and a basis for further studies associated with PGC-1α in digestive system cancers.

Keywords: PGC-1α, cancer, digestive system, metabolism, colorectal cancer, liver cancer.

Graphical Abstract
Puigserver, P.; Wu, Z.; Park, C.W.; Graves, R.; Wright, M.; Spiegelman, B.M. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell, 1998, 92(6), 829-839.
[] [PMID: 9529258]
Andersson, U.; Scarpulla, R.C. Pgc-1-related coactivator, a novel, serum-inducible coactivator of nuclear respiratory factor 1-dependent transcription in mammalian cells. Mol. Cell. Biol., 2001, 21(11), 3738-3749.
[] [PMID: 11340167]
Lin, J.; Puigserver, P.; Donovan, J.; Tarr, P.; Spiegelman, B.M. Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta), a novel PGC-1-related transcription coactivator associated with host cell factor. J. Biol. Chem., 2002, 277(3), 1645-1648.
[] [PMID: 11733490]
Houten, S.M.; Auwerx, J. PGC-1alpha: Turbocharging mitochondria. Cell, 2004, 119(1), 5-7.
[] [PMID: 15454076]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin., 2018, 68(1), 7-30.
[] [PMID: 29313949]
Schwingshackl, L.; Schwedhelm, C.; Hoffmann, G.; Knüppel, S.; Laure Preterre, A.; Iqbal, K.; Bechthold, A.; De Henauw, S.; Michels, N.; Devleesschauwer, B.; Boeing, H.; Schlesinger, S. Food groups and risk of colorectal cancer. Int. J. Cancer, 2018, 142(9), 1748-1758.
[] [PMID: 29210053]
Lin, Y.; Totsuka, Y.; Shan, B.; Wang, C.; Wei, W.; Qiao, Y.; Kikuchi, S.; Inoue, M.; Tanaka, H.; He, Y. Esophageal cancer in high-risk areas of China: Research progress and challenges. Ann. Epidemiol., 2017, 27(3), 215-221.
[] [PMID: 28007352]
Ward, P.S.; Thompson, C.B. Metabolic reprogramming: A cancer hallmark even warburg did not anticipate. Cancer Cell, 2012, 21(3), 297-308.
[] [PMID: 22439925]
Fernandez-Marcos, P.J.; Auwerx, J. Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. Am. J. Clin. Nutr., 2011, 93(4), 884S-90.
[] [PMID: 21289221]
Martínez-Redondo, V.; Pettersson, A.T.; Ruas, J.L. The hitchhiker’s guide to PGC-1α isoform structure and biological functions. Diabetologia, 2015, 58(9), 1969-1977.
[] [PMID: 26109214]
Wu, H.; Deng, X.; Shi, Y.; Su, Y.; Wei, J.; Duan, H. PGC-1α, glucose metabolism and type 2 diabetes mellitus. J. Endocrinol., 2016, 229(3), R99-R115.
[] [PMID: 27094040]
Cantó, C.; Auwerx, J. PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr. Opin. Lipidol., 2009, 20(2), 98-105.
[] [PMID: 19276888]
Villena, J.A. New insights into PGC-1 coactivators: Redefining their role in the regulation of mitochondrial function and beyond. FEBS J., 2015, 282(4), 647-672.
[] [PMID: 25495651]
Choong, C.J.; Mochizuki, H. Gene therapy targeting mitochondrial pathway in Parkinson’s disease. J. Neural Transm. (Vienna), 2017, 124(2), 193-207.
[] [PMID: 27638713]
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell, 2011, 144(5), 646-674.
[] [PMID: 21376230]
Pavlova, N.N.; Thompson, C.B. The emerging hallmarks of cancer metabolism. Cell Metab., 2016, 23(1), 27-47.
[] [PMID: 26771115]
Hay, N. Reprogramming glucose metabolism in cancer: Can it be exploited for cancer therapy? Nat. Rev. Cancer, 2016, 16(10), 635-649.
[] [PMID: 27634447]
Tan, Z.; Luo, X.; Xiao, L.; Tang, M.; Bode, A.M.; Dong, Z.; Cao, Y. The role of PGC1α in cancer metabolism and its therapeutic implications. Mol. Cancer Ther., 2016, 15(5), 774-782.
[] [PMID: 27197257]
Ferlay, J.; Soerjomataram, I.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D.M.; Forman, D.; Bray, F. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer, 2015, 136(5), E359-E386.
[] [PMID: 25220842]
Kelly, D.P.; Scarpulla, R.C. Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev., 2004, 18(4), 357-368.
[] [PMID: 15004004]
Feilchenfeldt, J.; Bründler, M.A.; Soravia, C.; Tötsch, M.; Meier, C.A. Peroxisome proliferator-activated receptors (PPARs) and associated transcription factors in colon cancer: Reduced expression of PPARgamma-coactivator 1 (PGC-1). Cancer Lett., 2004, 203(1), 25-33.
[] [PMID: 14670614]
D’Errico, I.; Salvatore, L.; Murzilli, S.; Lo Sasso, G.; Latorre, D.; Martelli, N.; Egorova, A.V.; Polishuck, R.; Madeyski-Bengtson, K.; Lelliott, C.; Vidal-Puig, A.J.; Seibel, P.; Villani, G.; Moschetta, A. Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1alpha) is a metabolic regulator of intestinal epithelial cell fate. Proc. Natl. Acad. Sci. USA, 2011, 108(16), 6603-6608.
[] [PMID: 21467224]
D’Errico, I.; Lo Sasso, G.; Salvatore, L.; Murzilli, S.; Martelli, N.; Cristofaro, M.; Latorre, D.; Villani, G.; Moschetta, A. Bax is necessary for PGC1α pro-apoptotic effect in colorectal cancer cells. Cell Cycle, 2011, 10(17), 2937-2945.
[] [PMID: 21862870]
Shin, S.W.; Yun, S.H.; Park, E.S.; Jeong, J.S.; Kwak, J.Y.; Park, J.I. Overexpression of PGC1α enhances cell proliferation and tumorigenesis of HEK293 cells through the upregulation of Sp1 and Acyl-CoA binding protein. Int. J. Oncol., 2015, 46(3), 1328-1342.
[] [PMID: 25585584]
Bhalla, K.; Hwang, B.J.; Dewi, R.E.; Ou, L.; Twaddel, W.; Fang, H.B.; Vafai, S.B.; Vazquez, F.; Puigserver, P.; Boros, L.; Girnun, G.D. PGC1α promotes tumor growth by inducing gene expression programs supporting lipogenesis. Cancer Res., 2011, 71(21), 6888-6898.
[] [PMID: 21914785]
Yun, S.H.; Roh, M.S.; Jeong, J.S.; Park, J.I. Peroxisome proliferator-activated receptor γ coactivator-1α is a predictor of lymph node metastasis and poor prognosis in human colorectal cancer. Ann. Diagn. Pathol., 2018, 33, 11-16.
[] [PMID: 29566941]
Yun, S.H.; Shin, S.W.; Park, J.I. Expression of fatty acid synthase is regulated by PGC1α and contributes to increased cell proliferation. Oncol. Rep., 2017, 38(6), 3497-3506.
[] [PMID: 29130104]
Nemoto, S.; Fergusson, M.M.; Finkel, T. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1alpha. J. Biol. Chem., 2005, 280(16), 16456-16460.
[] [PMID: 15716268]
Vellinga, T.T.; Borovski, T.; de Boer, V.C.J.; Fatrai, S.; van Schelven, S.; Trumpi, K.; Verheem, A.; Snoeren, N.; Emmink, B.L.; Koster, J.; Rinkes, I.H.M.B.; Kranenburg, O. SIRT1/PGC1α-dependent increase in oxidative phosphorylation supports chemotherapy resistance of colon cancer. Clin. Cancer Res., 2015, 21(12), 2870-2879.
[] [PMID: 25779952]
Yun, C.W.; Han, Y.S.; Lee, S.H. PGC-1 alpha controls mitochondrial biogenesis in drug-resistant colorectal cancer cells by regulating endoplasmic reticulum stress. Int. J. Mol. Sci., 2019, 20(7) pii: E1707
[] [PMID: 30959809]
Do, M.T.; Kim, H.G.; Choi, J.H.; Jeong, H.G. Metformin induces microRNA-34a to downregulate the Sirt1/Pgc-1α/Nrf2 pathway, leading to increased susceptibility of wild-type p53 cancer cells to oxidative stress and therapeutic agents. Free Radic. Biol. Med., 2014, 74, 21-34.
[] [PMID: 24970682]
Cho, Y.A.; Lee, J.; Oh, J.H.; Chang, H.J.; Sohn, D.K.; Shin, A.; Kim, J. Genetic variation in PPARGC1A may affect the role of diet-associated inflammation in colorectal carcinogenesis. Oncotarget, 2017, 8(5), 8550-8558.
[] [PMID: 28051997]
Liu, R.; Zhang, H.; Zhang, Y.; Li, S.; Wang, X.; Wang, X.; Wang, C.; Liu, B.; Zen, K.; Zhang, C.Y.; Zhang, C.; Ba, Y. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha acts as a tumor suppressor in hepatocellular carcinoma. Tumour Biol., 2017, 39(4) 1010428317695031
[] [PMID: 28381162]
Li, Y.; Xu, S.; Li, J.; Zheng, L.; Feng, M.; Wang, X.; Han, K.; Pi, H.; Li, M.; Huang, X.; You, N.; Tian, Y.; Zuo, G.; Li, H.; Zhao, H.; Deng, P.; Yu, Z.; Zhou, Z.; Liang, P. SIRT1 facilitates hepatocellular carcinoma metastasis by promoting PGC-1α-mediated mitochondrial biogenesis. Oncotarget, 2016, 7(20), 29255-29274.
[] [PMID: 27081083]
Lee, H.J.; Su, Y.; Lui, W.Y.; Chau, G.Y.; Yin, P.H.; Lee, H.C.; Chi, C.W. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1alpha) upregulated E-cadherin expression in HepG2 cells. FEBS Lett., 2008, 582(5), 627-634.
[] [PMID: 18242180]
Lee, H.J.; Su, Y.; Yin, P.H.; Lee, H.C.; Chi, C.W. PPAR(gamma)/PGC-1(alpha) pathway in E-cadherin expression and motility of HepG2 cells. Anticancer Res., 2009, 29(12), 5057-5063.
[PMID: 20044617]
Rafacho, B.P.; Stice, C.P.; Liu, C.; Greenberg, A.S.; Ausman, L.M.; Wang, X.D. Inhibition of diethylnitrosamine-initiated alcohol-promoted hepatic inflammation and precancerous lesions by flavonoid luteolin is associated with increased sirtuin 1 activity in mice. Hepatobiliary Surg. Nutr., 2015, 4(2), 124-134.
[PMID: 26005679]
Wang, G.L.; Salisbury, E.; Shi, X.; Timchenko, L.; Medrano, E.E.; Timchenko, N.A. HDAC1 promotes liver proliferation in young mice via interactions with C/EBPbeta. J. Biol. Chem., 2008, 283(38), 26179-26187.
[] [PMID: 18622014]
Jones, K.; Timchenko, L.; Timchenko, N.A. The role of CUGBP1 in age-dependent changes of liver functions. Ageing Res. Rev., 2012, 11(4), 442-449.
[] [PMID: 22446383]
Jin, J.; Iakova, P.; Jiang, Y.; Lewis, K.; Sullivan, E.; Jawanmardi, N.; Donehower, L.; Timchenko, L.; Timchenko, N.A. Transcriptional and translational regulation of C/EBPβ-HDAC1 protein complexes controls different levels of p53, SIRT1, and PGC1α proteins at the early and late stages of liver cancer. J. Biol. Chem., 2013, 288(20), 14451-14462.
[] [PMID: 23564453]
Kumar, A.; Giri, S.; Shaha, C. Sestrin2 facilitates glutamine-dependent transcription of PGC-1α and survival of liver cancer cells under glucose limitation. FEBS J., 2018, 285(7), 1326-1345.
[] [PMID: 29436167]
Mays, S.G.; Okafor, C.D.; Tuntland, M.L.; Whitby, R.J.; Dharmarajan, V.; Stec, J.; Griffin, P.R.; Ortlund, E.A. Structure and dynamics of the liver receptor homolog 1-PGC1α complex. Mol. Pharmacol., 2017, 92(1), 1-11.
[] [PMID: 28363985]
Yimlamai, D.; Fowl, B.H.; Camargo, F.D. Emerging evidence on the role of the Hippo/YAP pathway in liver physiology and cancer. J. Hepatol., 2015, 63(6), 1491-1501.
[] [PMID: 26226451]
Dong, J.; Feldmann, G.; Huang, J.; Wu, S.; Zhang, N.; Comerford, S.A.; Gayyed, M.F.; Anders, R.A.; Maitra, A.; Pan, D. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell, 2007, 130(6), 1120-1133.
[] [PMID: 17889654]
Hu, Y.; Shin, D.J.; Pan, H.; Lin, Z.; Dreyfuss, J.M.; Camargo, F.D.; Miao, J.; Biddinger, S.B. YAP suppresses gluconeogenic gene expression through PGC1α. Hepatology, 2017, 66(6), 2029-2041.
[] [PMID: 28714135]
González, C.A.; Sala, N.; Rokkas, T. Gastric cancer: Epidemiologic aspects. Helicobacter, 2013, 18(Suppl. 1), 34-38.
[] [PMID: 24011243]
Wang, P.; Guo, X.; Zong, W.; Li, Y.; Liu, G.; Lv, Y.; Zhu, Y.; He, S. PGC-1α/SNAI1 axis regulates tumor growth and metastasis by targeting miR-128b in gastric cancer. J. Cell. Physiol., 2019, 234(10), 17232-17241.
[] [PMID: 30684287]
Jiang, W.G.; Li, X.; Mansel, R.E. PGC1, peroxisome proliferator activated receptor-gamma (PPAR-gamma) coactivator-1, Is necessary in PPAR-gamma modulated angiogenesis. Cancer Res., 2011, 71(24), P2-05-02.
Yu, H.; Xin, Y. Down-regulated expressions of PPARγ and its coactivator PGC-1 are related to gastric carcinogenesis and Lauren’s classification in gastric carcinoma. Chin. J. Cancer Res., 2013, 25(6), 704-714.
[PMID: 24385698]
Yao, L.; Liu, F.; Sun, L.; Wu, H.; Guo, C.; Liang, S.; Liu, L.; Liu, N.; Han, Z.; Zhang, H.; Wu, K.; Fan, D. Upregulation of PPARgamma in tissue with gastric carcinoma. Hybridoma (Larchmt.), 2010, 29(4), 341-343.
[] [PMID: 20715992]
Lu, J.; Imamura, K.; Nomura, S.; Mafune, K.; Nakajima, A.; Kadowaki, T.; Kubota, N.; Terauchi, Y.; Ishii, G.; Ochiai, A.; Esumi, H.; Kaminishi, M. Chemopreventive effect of peroxisome proliferator-activated receptor gamma on gastric carcinogenesis in mice. Cancer Res., 2005, 65(11), 4769-4774.
[] [PMID: 15930296]
He, Q.; Chen, J.; Lin, H.L.; Hu, P.J.; Chen, M.H. Expression of peroxisome proliferator-activated receptor gamma, E-cadherin and matrix metalloproteinases-2 in gastric carcinoma and lymph node metastases. Chin. Med. J. (Engl.), 2007, 120(17), 1498-1504.
[] [PMID: 17908458]
Ramachandran, L.; Manu, K.A.; Shanmugam, M.K.; Li, F.; Siveen, K.S.; Vali, S.; Kapoor, S.; Abbasi, T.; Surana, R.; Smoot, D.T.; Ashktorab, H.; Tan, P.; Ahn, K.S.; Yap, C.W.; Kumar, A.P.; Sethi, G. Isorhamnetin inhibits proliferation and invasion and induces apoptosis through the modulation of peroxisome proliferator-activated receptor γ activation pathway in gastric cancer. J. Biol. Chem., 2012, 287(45), 38028-38040.
[] [PMID: 22992727]
Rahib, L.; Smith, B.D.; Aizenberg, R.; Rosenzweig, A.B.; Fleshman, J.M.; Matrisian, L.M. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res., 2014, 74(11), 2913-2921.
[] [PMID: 24840647]
Sancho, P.; Burgos-Ramos, E.; Tavera, A.; Bou Kheir, T.; Jagust, P.; Schoenhals, M.; Barneda, D.; Sellers, K.; Campos-Olivas, R.; Graña, O.; Viera, C.R.; Yuneva, M.; Sainz, B., Jr; Heeschen, C. MYC/PGC-1α balance determines the metabolic phenotype and plasticity of pancreatic cancer stem cells. Cell Metab., 2015, 22(4), 590-605.
[] [PMID: 26365176]
Huang, B.; Cheng, X.; Wang, D.; Peng, M.; Xue, Z.; Da, Y.; Zhang, N.; Yao, Z.; Li, M.; Xu, A.; Zhang, R. Adiponectin promotes pancreatic cancer progression by inhibiting apoptosis via the activation of AMPK/Sirt1/PGC-1α signaling. Oncotarget, 2014, 5(13), 4732-4745.
[] [PMID: 25051362]
Hsueh, W.A.; Gupte, A.A. PGC-1α: The missing ingredient for mesenchymal stem cell-mediated angiogenesis. Diabetes, 2012, 61(5), 979-980.
[] [PMID: 22517649]
Arany, Z.; Foo, S.Y.; Ma, Y.; Ruas, J.L.; Bommi-Reddy, A.; Girnun, G.; Cooper, M.; Laznik, D.; Chinsomboon, J.; Rangwala, S.M.; Baek, K.H.; Rosenzweig, A.; Spiegelman, B.M. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature, 2008, 451(7181), 1008-1012.
[] [PMID: 18288196]
Mammoto, A.; Muyleart, M.; Kadlec, A.; Gutterman, D.; Mammoto, T. YAP1-TEAD1 signaling controls angiogenesis and mitochondrial biogenesis through PGC1α. Microvasc. Res., 2018, 119, 73-83.
[] [PMID: 29680477]
Ali, F.; Ali, N.S.; Bauer, A.; Boyle, J.J.; Hamdulay, S.S.; Haskard, D.O.; Randi, A.M.; Mason, J.C. PPARdelta and PGC1alpha act cooperatively to induce haem oxygenase-1 and enhance vascular endothelial cell resistance to stress. Cardiovasc. Res., 2010, 85(4), 701-710.
[] [PMID: 19903700]

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy