PI3K/AKT phosphorylation activates ERRα by upregulating PGC‑1α and PGC‑1β in gallbladder cancer

Wang,Lei; Yang,Mengmeng; Jin,Huihan

doi:10.3892/mmr.2021.12252

PI3K/AKT phosphorylation activates ERRα by upregulating PGC‑1α and PGC‑1β in gallbladder cancer

Authors:
- Lei Wang
- Mengmeng Yang
- Huihan Jin
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Affiliations: Department of Hepatobiliary Surgery, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, Jiangsu 214002, P.R. China, Department of Malaria Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology (Jiangsu Institute of Parasitic Diseases), Wuxi, Jiangsu 214002, P.R. China
Published online on: June 28, 2021 https://doi.org/10.3892/mmr.2021.12252
Article Number: 613
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The nuclear estrogen‑related receptor‑α (ERRα) is an orphan receptor that has been identified as a transcriptional factor. Peroxisome proliferator‑activated receptor‑γ (PPARγ) coactivator‑1‑α (PGC‑1α) and PPARγ coactivator‑1‑β (PGC‑1β) act as the co‑activators of ERRα. Our previous study reported that activated ERRα promoted the invasion and proliferation of gallbladder cancer cells by promoting PI3K/AKT phosphorylation. Therefore, the aim of the current study was to investigate whether PI3K/AKT phosphorylation could enhance ERRα activity in a positive feedback loop. LY294002 and insulin‑like growth factor I (IGF‑I) were used to inhibit and promote PI3K/AKT phosphorylation, respectively. A 3X ERE‑TATA luciferase reporter was used to measure ERRα activity. The present study found that LY294002 inhibited PI3K/AKT phosphorylation, decreased the proliferation and invasion of NOZ cells and suppressed the activity of ERRα. Conversely, IGF‑I induced PI3K/AKT phosphorylation, promoted the proliferation and invasion of NOZ cells and enhanced the activity of ERRα. The protein expression levels of PGC‑1α and PGC‑1β were elevated and reduced by IGF‑I and LY294002, respectively. Moreover, knockdown of PGC‑1α and PGC‑1β antagonized ERRα activation, which was enhanced by PI3K/AKT phosphorylation. Taken together, the present study demonstrated that PI3K/AKT phosphorylation triggered ERRα by upregulating the expression levels of PGC‑1α and PGC‑1β in NOZ cells.

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1	Ouyang G, Liu Q, Wu Y, Liu Z, Lu W, Li S, Pan G and Chen X: The global, regional, and national burden of gallbladder and biliary tract cancer and its attributable risk factors in 195 countries and territories, 1990 to 2017: A systematic analysis for the Global Burden of Disease Study 2017. Cancer. 127:2238–2250. 2021. View Article : Google Scholar : PubMed/NCBI
2	Baiu I and Visser B: Gallbladder cancer. JAMA. 320:12942018. View Article : Google Scholar : PubMed/NCBI
3	Zhang X, Kong Z, Xu X, Yun X, Chao J, Ding D, Li T, Gao Y, Guan N, Zhu C and Qin X: ARRB1 drives gallbladder cancer progression by facilitating TAK1/MAPK signaling activation. J Cancer. 12:1926–1935. 2021. View Article : Google Scholar : PubMed/NCBI
4	Sharma A, Sharma KL, Gupta A, Yadav A and Kumar A: Gallbladder cancer epidemiology, pathogenesis and molecular genetics: Recent update. World J Gastroenterol. 23:3978–3998. 2017. View Article : Google Scholar : PubMed/NCBI
5	Hu YP, Jin YP, Wu XS, Yang Y, Li YS, Li HF, Xiang SS, Song XL, Jiang L, Zhang YJ, et al: LncRNA-HGBC stabilized by HuR promotes gallbladder cancer progression by regulating miR-502-3p/SET/AKT axis. Mol Cancer. 18:1672019. View Article : Google Scholar : PubMed/NCBI
6	Kim M, Kim H, Han Y, Sohn H, Kang JS, Kwon W and Jang JY: Prognostic value of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) in gallbladder cancer; 65 IU/ml of CA 19-9 is the new cut-off value for prognosis. Cancers (Basel). 13:10892021. View Article : Google Scholar : PubMed/NCBI
7	Li M, Liu F, Zhang F, Zhou W, Jiang X, Yang Y, Qu K, Wang Y, Ma Q, Wang T, et al: Genomic ERBB2/ERBB3 mutations promote PD-L1-mediated immune escape in gallbladder cancer: A whole-exome sequencing analysis. Gut. 68:1024–1033. 2019. View Article : Google Scholar : PubMed/NCBI
8	Chen X, Wu X, Wu H, Gu Y, Shao Y, Shao Q, Zhu F, Li X, Qian X, Hu J, et al: Camrelizumab plus gemcitabine and oxaliplatin (GEMOX) in patients with advanced biliary tract cancer: A single-arm, open-label, phase II trial. J Immunother Cancer. 8:e0012402020. View Article : Google Scholar : PubMed/NCBI
9	Giguère V, Yang N, Segui P and Evans RM: Identification of a new class of steroid hormone receptors. Nature. 331:91–94. 1988. View Article : Google Scholar
10	Deblois G and Giguère V: Functional and physiological genomics of estrogen-related receptors (ERRs) in health and disease. Biochim Biophys Acta. 1812:1032–1040. 2011. View Article : Google Scholar : PubMed/NCBI
11	Kim SY, Yang CS, Lee HM, Kim JK, Kim YS, Kim YR, Kim JS, Kim TS, Yuk JM, Dufour CR, et al: ESRRA (estrogen-related receptor α) is a key coordinator of transcriptional and post-translational activation of autophagy to promote innate host defense. Autophagy. 14:152–168. 2018. View Article : Google Scholar : PubMed/NCBI
12	Deblois G, Hall JA, Perry MC, Laganière J, Ghahremani M, Park M, Hallett M and Giguère V: Genome-wide identification of direct target genes implicates estrogen-related receptor alpha as a determinant of breast cancer heterogeneity. Cancer Res. 69:6149–6157. 2009. View Article : Google Scholar : PubMed/NCBI
13	Luo C, Widlund HR and Puigserver P: PGC-1 coactivators: Shepherding the mitochondrial biogenesis of tumors. Trends Cancer. 2:619–631. 2016. View Article : Google Scholar : PubMed/NCBI
14	Huss JM, Kopp RP and Kelly DP: Peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) coactivates the cardiac-enriched nuclear receptors estrogen-related receptor-alpha and -gamma. Identification of novel leucine-rich interaction motif within PGC-1alpha. J Biol Chem. 277:40265–40274. 2002. View Article : Google Scholar : PubMed/NCBI
15	Yang Y, Li S, Li B, Li Y, Xia K, Aman S, Yang Y, Ahmad B, Zhao B and Wu H: FBXL10 promotes ERRα protein stability and proliferation of breast cancer cells by enhancing the mono-ubiquitylation of ERRα. Cancer Lett. 502:108–119. 2021. View Article : Google Scholar : PubMed/NCBI
16	Gaillard S, Grasfeder LL, Haeffele CL, Lobenhofer EK, Chu TM, Wolfinger R, Kazmin D, Koves TR, Muoio DM, Chang CY, et al: Receptor-selective coactivators as tools to define the biology of specific receptor-coactivator pairs. Mol Cell. 24:797–803. 2006. View Article : Google Scholar : PubMed/NCBI
17	Mayer IA and Arteaga CL: The PI3K/AKT pathway as a target for cancer treatment. Annu Rev Med. 67:11–28. 2016. View Article : Google Scholar : PubMed/NCBI
18	Yang F, Xie HY, Yang LF, Zhang L, Zhang FL, Liu HY, Li DQ and Shao ZM: Stabilization of MORC2 by estrogen and antiestrogens through GPER1-PRKACA-CMA pathway contributes to estrogen-induced proliferation and endocrine resistance of breast cancer cells. Autophagy. 16:1061–1076. 2020. View Article : Google Scholar : PubMed/NCBI
19	Xia P, Gütl D, Zheden V and Heisenberg CP: Lateral inhibition in cell specification mediated by mechanical signals modulating TAZ activity. Cell. 176:1379–1392.e14. 2019. View Article : Google Scholar : PubMed/NCBI
20	Lu Y, Tao F, Zhou MT and Tang KF: The signaling pathways that mediate the anti-cancer effects of caloric restriction. Pharmacol Res. 141:512–520. 2019. View Article : Google Scholar : PubMed/NCBI
21	Girnita L, Worrall C, Takahashi S, Seregard S and Girnita A: Something old, something new and something borrowed: Emerging paradigm of insulin-like growth factor type 1 receptor (IGF-1R) signaling regulation. Cell Mol Life Sci. 71:2403–2427. 2014. View Article : Google Scholar : PubMed/NCBI
22	LeRoith D, Werner H, Beitner-Johnson D and Roberts CT Jr: Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev. 16:143–163. 1995. View Article : Google Scholar : PubMed/NCBI
23	Myers MG Jr, Backer JM, Sun XJ, Shoelson S, Hu P, Schlessinger J, Yoakim M, Schaffhausen B and White MF: IRS-1 activates phosphatidylinositol 3′-kinase by associating with src homology 2 domains of p85. Proc Natl Acad Sci USA. 89:10350–10354. 1992. View Article : Google Scholar : PubMed/NCBI
24	Vanhaesebroeck B and Alessi DR: The PI3K-PDK1 connection: More than just a road to PKB. Biochem J. 346:561–576. 2000. View Article : Google Scholar : PubMed/NCBI
25	Wang L, Yang M, Guo X, Yang Z, Liu S, Ji Y and Jin H: Estrogen-related receptor-α promotes gallbladder cancer development by enhancing the transcription of Nectin-4. Cancer Sci. 111:1514–1527. 2020. View Article : Google Scholar : PubMed/NCBI
26	Zhang Y, Liu S, Wang L, Wu Y, Hao J, Wang Z, Lu W, Wang XA, Zhang F, Cao Y, et al: A novel PI3K/AKT signaling axis mediates Nectin-4-induced gallbladder cancer cell proliferation, metastasis and tumor growth. Cancer Lett. 375:179–189. 2016. View Article : Google Scholar : PubMed/NCBI
27	Chang CY, Kazmin D, Jasper JS, Kunder R, Zuercher WJ and McDonnell DP: The metabolic regulator ERRα, a downstream target of HER2/IGF-1R, as a therapeutic target in breast cancer. Cancer Cell. 20:500–510. 2011. View Article : Google Scholar : PubMed/NCBI
28	Theodoris CV, Zhou P, Liu L, Zhang Y, Nishino T, Huang Y, Kostina A, Ranade SS, Gifford CA, Uspenskiy V, et al: Network-based screen in iPSC-derived cells reveals therapeutic candidate for heart valve disease. Science. 371:eabd07242021. View Article : Google Scholar : PubMed/NCBI
29	Ramaswamy A, Ostwal V, Sharma A, Bhargava P, Srinivas S, Goel M, Patkar S, Mandavkar S, Jadhav P, Parulekar M, et al: Efficacy of capecitabine plus irinotecan vs irinotecan monotherapy as second-line treatment in patients with advanced gallbladder cancer: A multicenter phase 2 randomized clinical trial (GB-SELECT). JAMA Oncol. 7:436–439. 2021. View Article : Google Scholar : PubMed/NCBI
30	Nepal C, Zhu B, O'Rourke CJ, Bhatt DK, Lee D, Song L, Wang D, Van Dyke A, Choo-Wosoba H, Liu Z, et al: Integrative molecular characterization of gallbladder cancer reveals microenvironment-associated subtypes. J Hepatol. 74:1132–1144. 2021. View Article : Google Scholar : PubMed/NCBI
31	Ranhotra HS: Estrogen-related receptor alpha and cancer: Axis of evil. J Recept Signal Transduct Res. 35:505–508. 2015. View Article : Google Scholar : PubMed/NCBI
32	Mercurio L, Albanesi C and Madonna S: Recent updates on the involvement of PI3K/AKT/mTOR molecular cascade in the pathogenesis of hyperproliferative skin disorders. Front Med (Lausanne). 8:6656472021. View Article : Google Scholar : PubMed/NCBI
33	Song M, Bode AM, Dong Z and Lee MH: AKT as a therapeutic target for cancer. Cancer Res. 79:1019–1031. 2019. View Article : Google Scholar : PubMed/NCBI
34	Villena JA: New insights into PGC-1 coactivators: Redefining their role in the regulation of mitochondrial function and beyond. FEBS J. 282:647–672. 2015. View Article : Google Scholar : PubMed/NCBI
35	Lin J, Handschin C and Spiegelman BM: Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 1:361–370. 2005. View Article : Google Scholar : PubMed/NCBI
36	Patten IS and Arany Z: PGC-1 coactivators in the cardiovascular system. Trends Endocrinol Metab. 23:90–97. 2012. View Article : Google Scholar : PubMed/NCBI
37	Li S, Liu C, Li N, Hao T, Han T, Hill DE, Vidal M and Lin JD: Genome-wide coactivation analysis of PGC-1alpha identifies BAF60a as a regulator of hepatic lipid metabolism. Cell Metab. 8:105–117. 2008. View Article : Google Scholar : PubMed/NCBI
38	Vernier M and Giguère V: Aging, senescence and mitochondria: The PGC-1/ERR axis. J Mol Endocrinol. 66:R1–R14. 2021. View Article : Google Scholar : PubMed/NCBI
39	Chambers JM and Wingert RA: PGC-1α in disease: Recent renal insights into a versatile metabolic regulator. Cells. 9:22342020. View Article : Google Scholar : PubMed/NCBI