G-Protein-Coupled Estrogen Receptor 1 Promotes Gender Disparities in Hepatocellular Carcinoma via Modulation of SIN1 and mTOR Complex 2 Activity.
Adaptor Proteins, Signal Transducing
/ chemistry
Animals
Carcinoma, Hepatocellular
/ genetics
Cell Line, Tumor
Estrogen Receptor alpha
/ metabolism
Estrogens
/ pharmacology
Female
Hep G2 Cells
Humans
Liver Neoplasms
/ genetics
Male
Mechanistic Target of Rapamycin Complex 2
/ metabolism
Mice
Neoplasm Transplantation
Protein Stability
Proto-Oncogene Proteins c-akt
/ metabolism
Receptors, Estrogen
/ metabolism
Receptors, G-Protein-Coupled
/ metabolism
Sex Characteristics
Signal Transduction
Up-Regulation
Journal
Molecular cancer research : MCR
ISSN: 1557-3125
Titre abrégé: Mol Cancer Res
Pays: United States
ID NLM: 101150042
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
22
02
2020
revised:
30
06
2020
accepted:
25
08
2020
pubmed:
3
9
2020
medline:
28
9
2021
entrez:
3
9
2020
Statut:
ppublish
Résumé
Due to its intricate heterogeneity and limited treatment, hepatocellular carcinoma (HCC) has been considered a major cause of cancer-related mortality worldwide. Increasing evidence indicates that G-protein-coupled estrogen receptor 1 (GPER1) can promote estrogen-dependent hepatocellular proliferation by activating AKT signaling. The mTOR complex 2 (mTORC2), whose integrity and activity are modulated by its subunit Sin1, controls the activation of AKT by phosphorylation at position S473. In this study, we investigate the modulation of Sin1 and how estrogen signaling may influence the mTORC2-AKT cascade in HCC cells and a DEN-induced mouse model. We have found that estradiol-dependent Sin1 expression is transcriptionally modulated by GPER1 as well as ERα. GPER1 is able to regulate Sin1 stability via nuclear translocation, therefore increasing Sin1-mTORC2-AKT activation. Moreover, Sin1 interacts with ERα and further enhances its transcriptional activity. Sin1 is highly expressed in acute liver injury and in cases of HCC harboring high expression of GPER1 and constitutive activation of mTORC2-AKT signaling. GPER1 inhibition using the antagonist G-15 reverses DEN-induced acute liver injury by suppressing Sin1 expression and mTORC2-AKT activation. Notably,
Identifiants
pubmed: 32873626
pii: 1541-7786.MCR-20-0173
doi: 10.1158/1541-7786.MCR-20-0173
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
ESR1 protein, human
0
Estrogen Receptor alpha
0
Estrogens
0
GPER1 protein, human
0
MAPKAP1 protein, human
0
Receptors, Estrogen
0
Receptors, G-Protein-Coupled
0
Mechanistic Target of Rapamycin Complex 2
EC 2.7.11.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1863-1875Informations de copyright
©2020 American Association for Cancer Research.
Références
Ruggieri A, Barbati C, Malorni W. Cellular and molecular mechanisms involved in hepatocellular carcinoma gender disparity. Int J Cancer. 2010;127:499–504.
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86.
Fares N, Peron JM. [Epidemiology, natural history, and risk factors of hepatocellular carcinoma]. Rev Prat. 2013;63:216–7.
Wang Z, Kim J, Teng Y, Ding HF, Zhang J, Hai T, et al. Loss of ATF3 promotes hormone-induced prostate carcinogenesis and the emergence of CK5(+)CK8(+) epithelial cells. Oncogene. 2016;35:3555–64.
Ozdemir BC, Dotto GP. Sex hormones and anticancer immunity. Clin Cancer Res. 2019;25:4603–10.
Ma WL, Hsu CL, Wu MH, Wu CT, Wu CC, Lai JJ, et al. Androgen receptor is a new potential therapeutic target for the treatment of hepatocellular carcinoma. Gastroenterology. 2008;135:947–55.
Ma WL, Hsu CL, Yeh CC, Wu MH, Huang CK, Jeng LB, et al. Hepatic androgen receptor suppresses hepatocellular carcinoma metastasis through modulation of cell migration and anoikis. Hepatology. 2012;56:176–85.
Castagnetta LA, Agostara B, Montalto G, Polito L, Campisi I, Saetta A, et al. Local estrogen formation by nontumoral, cirrhotic, and malignant human liver tissues and cells. Cancer Res. 2003;63:5041–5.
Francavilla A, Panella C, Polimeno L, Giangaspero A, Mazzaferro V, Pan CE, et al. Hormonal and enzymatic parameters of hepatic regeneration in patients undergoing major liver resections. Hepatology. 1990;12:1134–8.
Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science. 2007;317:121–4.
Iyer JK, Kalra M, Kaul A, Payton ME, Kaul R. Estrogen receptor expression in chronic hepatitis C and hepatocellular carcinoma pathogenesis. World J Gastroenterol. 2017;23:6802–16.
Zheng B, Zhu YJ, Wang HY, Chen L. Gender disparity in hepatocellular carcinoma (HCC): multiple underlying mechanisms. Sci China Life Sci. 2017;60:575–84.
Huang P, Xu Q, Yan Y, Lu Y, Hu Z, Ou B, et al. HBx/ERα complex-mediated LINC01352 downregulation promotes HBV-related hepatocellular carcinoma via the miR-135b-APC axis. Oncogene. 2020;39:3774–89.
Feng H, Yu Z, Tian Y, Lee YY, Li MS, Go MY, et al. A CCRK-EZH2 epigenetic circuitry drives hepatocarcinogenesis and associates with tumor recurrence and poor survival of patients. J Hepatol. 2015;62:1100–11.
Prossnitz ER, Maggiolini M. Mechanisms of estrogen signaling and gene expression via GPR30. Mol Cell Endocrinol. 2009;308:32–8.
Lam HM, Ouyang B, Chen J, Ying J, Wang J, Wu CL, et al. Targeting GPR30 with G-1: a new therapeutic target for castration-resistant prostate cancer. Endocr Relat Cancer. 2014;21:903–14.
Liu C, Liao Y, Fan S, Fu X, Xiong J, Zhou S, et al. G-protein-coupled estrogen receptor antagonist G15 decreases estrogen-induced development of non-small cell lung cancer. Oncol Res. 2019;27:283–92.
Zheng Y, Houston KD. Glucose-dependent GPER1 expression modulates tamoxifen-induced IGFBP-1 accumulation. J Mol Endocrinol. 2019;63:103–12.
Chaturantabut S, Shwartz A, Evason KJ, Cox AG, Labella K, Schepers AG, et al. Estrogen activation of G-protein-coupled estrogen receptor 1 regulates phosphoinositide 3-kinase and mTOR signaling to promote liver growth in zebrafish and proliferation of human hepatocytes. Gastroenterology. 2019;156:1788–804.
Matter MS, Decaens T, Andersen JB, Thorgeirsson SS. Targeting the mTOR pathway in hepatocellular carcinoma: current state and future trends. J Hepatol. 2014;60:855–65.
Xu Z, Xu M, Liu P, Zhang S, Shang R, Qiao Y, et al. The mTORC2-akt1 cascade is crucial for c-Myc to promote hepatocarcinogenesis in mice and humans. Hepatology. 2019;70:1600–13.
Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129:1261–74.
Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149:274–93.
Ben-Sahra I, Manning BD. mTORC1 signaling and the metabolic control of cell growth. Curr Opin Cell Biol. 2017;45:72–82.
Gaubitz C, Prouteau M, Kusmider B, Loewith R. TORC2 structure and function. Trends Biochem Sci. 2016;41:532–45.
Sarbassov DD, Ali SM, Kim D-H, Guertin DA, Latek RR, Erdjument-Bromage H, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol. 2004;14:1296–302.
Lin XM, Hu L, Gu J, Wang RY, Li L, Tang J, et al. Choline kinase alpha mediates interactions between the epidermal growth factor receptor and mechanistic target of rapamycin complex 2 in hepatocellular carcinoma cells to promote drug resistance and xenograft tumor progression. Gastroenterology. 2017;152:1187–202.
Guri Y, Colombi M, Dazert E, Hindupur SK, Roszik J, Moes S, et al. mTORC2 promotes tumorigenesis via lipid synthesis. Cancer Cell. 2017;32:807–23.
Liu P, Gan W, Inuzuka H, Lazorchak AS, Gao D, Arojo O, et al. Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis. Nat Cell Biol. 2013;15:1340–50.
Wang B, Jie Z, Joo D, Ordureau A, Liu P, Gan W, et al. TRAF2 and OTUD7B govern a ubiquitin-dependent switch that regulates mTORC2 signalling. Nature. 2017;545:365.
Wang D, Wu P, Wang H, Zhu L, Zhao W, Lu Y. SIN1 promotes the proliferation and migration of breast cancer cells by Akt activation. Biosci Rep. 2016;36:e00424.
Xu J, Li X, Yang H, Chang R, Kong C, Yang L. SIN1 promotes invasion and metastasis of hepatocellular carcinoma by facilitating epithelial‐mesenchymal transition. Cancer. 2013;119:2247–57.
Wang Q, Zhu J, Wang YW, Dai Y, Wang Y, Wang C, et al. Tumor suppressor Pdcd4 attenuates Sin1 translation to inhibit invasion in colon carcinoma. Oncogene. 2017;36:6225.
Hwang Y, Kim LC, Song W, Edwards DN, Cook RS, Chen J. Disruption of the scaffolding function of mLST8 selectively inhibits mTORC2 assembly and function and suppresses mTORC2-dependent tumor growth in vivo. Cancer Res. 2019;79:3178–84.
Fang Z, Zhang T, Dizeyi N, Chen S, Wang H, Swanson KD, et al. Androgen receptor enhances p27 degradation in prostate cancer cells through rapid and selective TORC2 activation. J Biol Chem. 2012;287:2090–8.
Wang Z, Yan J, Lin H, Hua F, Wang X, Liu H, et al. Toll-like receptor 4 activity protects against hepatocellular tumorigenesis and progression by regulating expression of DNA repair protein Ku70 in mice. Hepatology. 2013;57:1869–81.
Makino C, Sano Y, Shinagawa T, Millar JB, Ishii S. Sin1 binds to both ATF-2 and p38 and enhances ATF-2-dependent transcription in an SAPK signaling pathway. Genes Cells. 2006;11:1239–51.
Tu Y, Ji C, Yang B, Yang Z, Gu H, Lu CC, et al. DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-SIN1 association mediates ultraviolet B (UVB)-induced Akt Ser-473 phosphorylation and skin cell survival. Mol Cancer. 2013;12:172.
Chen TY, Lin CL, Wang LF, Tsai KL, Lin JY, Hsu C. Targeting GPER1 to suppress autophagy as a male-specific therapeutic strategy for iron-induced striatal injury. Sci Rep. 2019;9:6661.
Tian S, Zhan N, Li R, Dong W. Downregulation of G protein-coupled estrogen receptor (GPER) is associated with reduced prognosis in patients with gastric cancer. Med Sci Monit. 2019;25:3115–26.
Dong WH, Chen JC, He YL, Xu JJ, Mei YA. Resveratrol inhibits K(v)2.2 currents through the estrogen receptor GPR30-mediated PKC pathway. Am J Physiol Cell Physiol. 2013;305:C547–57.
Yin H, Zhu Q, Liu M, Tu G, Li Q, Yuan J, et al. GPER promotes tamoxifen-resistance in ER+ breast cancer cells by reduced Bim proteins through MAPK/Erk-TRIM2 signaling axis. Int J Oncol. 2017;51:1191–8.
Pei H, Wang W, Zhao D, Su H, Su G, Zhao Z. G Protein-coupled estrogen receptor 1 inhibits angiotensin II-induced cardiomyocyte hypertrophy via the regulation of PI3K-Akt-mTOR signalling and autophagy. Int J Biol Sci. 2019;15:81–92.
Yu T, Yang G, Hou Y, Tang X, Wu C, Wu XA, et al. Cytoplasmic GPER translocation in cancer-associated fibroblasts mediates cAMP/PKA/CREB/glycolytic axis to confer tumor cells with multidrug resistance. Oncogene. 2017;36:2131–45.
Peng J, Zuo Y, Huang L, Okada T, Liu S, Zuo G, et al. Activation of GPR30 with G1 attenuates neuronal apoptosis via src/EGFR/stat3 signaling pathway after subarachnoid hemorrhage in male rats. Exp Neurol. 2019;320:113008.
Liang S, Chen Z, Jiang G, Zhou Y, Liu Q, Su Q, et al. Activation of GPER suppresses migration and angiogenesis of triple negative breast cancer via inhibition of NF-kappaB/IL-6 signals. Cancer Lett. 2017;386:12–23.
Hu Z, Wang Y, Wang Y, Zang B, Hui H, You Z, et al. Epigenetic activation of SIN1 promotes NSCLC cell proliferation and metastasis by affecting the epithelial-mesenchymal transition. Biochem Biophys Res Commun. 2017;483:645–51.
Vinciguerra M, Foti M. PTEN at the crossroad of metabolic diseases and cancer in the liver. Ann Hepatol. 2008;7:192–9.
Cortes E, Lachowski D, Rice A, Thorpe SD, Robinson B, Yeldag G, et al. Tamoxifen mechanically deactivates hepatic stellate cells via the G protein-coupled estrogen receptor. Oncogene. 2019;38:2910–22.
Wei T, Chen W, Wen L, Zhang J, Zhang Q, Yang J, et al. G protein-coupled estrogen receptor deficiency accelerates liver tumorigenesis by enhancing inflammation and fibrosis. Cancer Lett. 2016;382:195–202.