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Effects of Estrogen and Estrogen Receptors on Glucose Metabolism of Liver Cancer Cell


Affiliations
1 Structural Biology Miami University, Oxford, Ohio, United States
2 Department of Biology, Miami University Oxford, Ohio, United States
 

Epidemiology data show that men have a much higher incidence of hepatocellular carcinoma (HCC) than women, suggesting that estrogen and its receptors may inhibit HCC development and progression. To investigate the potential inhibitory mechanisms of estrogens on HCC development, human cancer cell line HepG2 was treated with different concentrations of estrogen and specific agonists for estrogen receptor (ER) ERα and ERβ to determine the roles of estrogen and its receptors in HepG2 cancer cell proliferation, apoptosis, gene expression, and metabolic pathways. Our findings indicated that estrogen and its receptors suppressed HepG2 cell growth by inhibiting cell proliferation and stimulating cell apoptosis via primary activation of ERβ, and by affecting HepG2 glucose metabolism via primary activation of ERα. Identifying roles of different estrogen receptors would provide comprehensive understanding of estrogenic mechanisms in HCC development and shed light on potential treatments for HCC patients.

Keywords

HepG2, Estradiol, ERα, ERβ, Glycolysis, Oxidative Phosphorylation.
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  • H. B. El-Serag, "Hepatocellular carcinoma," N Engl J Med, vol. 365, pp. 1118-1127, 2011.

  • B. Njei, Y. Rotman, I. Ditah, and J. K. Lim, "Emerging trends in hepatocellular carcinoma incidence and mortality," Hepatology (Baltimore, Md.), vol. 61, pp. 191-199, 2015.

  • F. Z. Khan, R. B. Perumpail, R. J. Wong, and A. Ahmed, "Advances in hepatocellular carcinoma: Nonalcoholic steatohepatitis-related hepatocellular carcinoma," World J Hepatol, vol. 7, pp. 2155-2161, 2015.

  • E. Vanni and E. Bugianesi, "Obesity and liver cancer," Clin Liver Dis, vol. 18, pp. 191-203, 2014.

  • O. Warburg, "On respiratory impairment in cancer cells," Science, vol. 124, pp. 269-70, Aug 10 1956.

  • S. Weinhouse, "On respiratory impairment in cancer cells," Science, vol. 124, pp. 267-9, Aug 10 1956.

  • D. Hanahan and Robert A. Weinberg, "Hallmarks of cancer: the next generation," Cell, vol. 144, pp. 646674, 2011.

  • T. Pfeiffer, S. Schuster, and S. Bonhoeffer, "Cooperation and competition in the evolution of ATP-producing pathways," Science, vol. 292, pp. 504507, 2001.

  • X. L. Zu and M. Guppy, "Cancer metabolism: facts, fantasy, and fiction," Biochem Biophys Res Commun, vol. 313, pp. 459-465, 2004.

  • K. Suganuma, H. Miwa, N. Imai, M. Shikami, M. Gotou, M. Goto, S. Mizuno, M. Takahashi, H. Yamamoto, A. Hiramatsu, M. Wakabayashi, M. Watarai, I. Hanamura, A. Imamura, H. Mihara, and M. Nitta, "Energy metabolism of leukemia cells: glycolysis versus oxidative phosphorylation," Leuk Lymphoma, vol. 51, pp. 2112-2119, 2010/11/01 2010.

  • G. Weber, C. Allard, G. D. Lamirande, and A. Cantero, "Liver glucose-6-phosphatase activity and intracellular distribution after cortisone administration," Endocrinology, vol. 58, pp. 40-50, 1956.

  • J. W. Harding, E. A. Pyeritz, H. P. Morris, and H. B. White, "Proportional activities of glycerol kinase and glycerol 3-phosphate dehydrogenase in rat hepatomas," Biochem J, vol. 148, pp. 545-550, 1975.

  • B. Wang, S. Hsu, W. Frankel, K. Ghoshal, and S. T. Jacob, "Stat3-mediated activation of miR-23a suppresses gluconeogenesis in hepatocellular carcinoma by downregulating G6PC and PGC-1α," Hepatology (Baltimore, Md.), vol. 56, pp. 186-197, 2012.

  • G. Weber and A. Cantero, "Glucose-6-phosphatase activity in normal, pre-cancerous, and neoplastic tissues," Cancer Res, vol. 15, pp. 105-108, 1955.

  • G. Weber and H. P. Morris, "Comparative biochemistry of pepatomas. III. Carbohydrate enzymes in liver tumors of different growth rates," Cancer Res, vol. 23, pp. 987-994, 1963.

  • C. E. Shonk, H. P. Morris, and G. E. Boxer, "Patterns of glycolytic enzymes in rat liver and hepatoma," Cancer Res, vol. 25, pp. 671-676, 1965.

  • F. X. Bosch, J. Ribes, M. Díaz, and R. Cléries, "Primary liver cancer: Worldwide incidence and trends," Gastroenterology, vol. 127, pp. S5-S16, 2004.

  • I. Shimizu, M. Yasuda, Y. Mizobuchi, Y. Ma, F. Liu, M. Shiba, T. Horie, and S. Ito, "Suppressive effect of oestradiol on chemical hepatocarcinogenesis in rats," Gut, vol. 42, pp. 112-119, 1998.

  • M. Yasuda, I. Shimizu, M. Shiba, and S. Ito, "Suppressive effects of estradiol on dimethylnitrosamine-induced fibrosis of the liver in rats," Hepatology, vol. 29, pp. 719-727, 1999.

  • L. Mazzarella, "Why does obesity promote cancer? Epidemiology, biology, and open questions," ecancermedicalscience, vol. 9, p. 554, 2015.

  • M. Anbalagan and B. G. Rowan, "Estrogen receptor alpha phosphorylation and its functional impact in human breast cancer," Mol Cell Endocrinol, vol. 418, Part 3, pp. 264-272, 2015.

  • I. Persson, "Estrogens in the causation of breast, endometrial and ovarian cancers — evidence and hypotheses from epidemiological findings," J Steroid Biochem Mol Biol, vol. 74, pp. 357-364, 2000.

  • G. G. J. M. Kuiper, B. Carlsson, K. Grandien, E. Enmark, J. Häggblad, S. Nilsson, and J.-Å. Gustafsson, "Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta," Endocrinology, vol. 138, pp. 863-870, March 1, 1997 1997.

  • A. Blume, L. Torner, Y. Liu, S. Subburaju, G. Aguilera, and I. D. Neumann, "Prolactin activates mitogen-activated protein kinase signaling and corticotropin releasing hormone transcription in rat hypothalamic neurons," Endocrinology, vol. 150, pp. 1841-1849, April 1, 2009 2009.

  • D. Dondi, M. Piccolella, A. Biserni, S. Della Torre, B. Ramachandran, A. Locatelli, P. Rusmini, D. Sau, D. Caruso, A. Maggi, P. Ciana, and A. Poletti, "Estrogen receptor β and the progression of prostate cancer: role of 5α-androstane-3β,17β-diol," Endocr Relat Cancer, vol. 17, pp. 731-742, September 1, 2010 2010.

  • G. Lazennec, D. Bresson, A. Lucas, C. Chauveau, and F. Vignon, "ERβ inhibits proliferation and invasion of breast cancer cells," Endocrinology, vol. 142, pp. 4120-4130, 2001.

  • K. Hayashida, I. Shoji, L. Deng, D.-P. Jiang, Y.-H. Ide, and H. Hotta, "17β-estradiol inhibits the production of infectious particles of hepatitis C virus," Microbiol Immunol, vol. 54, pp. 684-690, 2010.

  • N. Altiok, M. Ersoz, and M. Koyuturk, "Estradiol induces JNK-dependent apoptosis in glioblastoma cells," Oncol Lett, vol. 2, pp. 1281-1285, 2011.

  • L. M. Prieto, J. W. Brown, C. Perez-Stable, and L. M. Fishman, "High dose17 β-estradiol and the α-estrogen agonist PPT trigger apoptosis in human adrenal carcinoma cells but the β-estrogen agonist DPN does not," Horm Metab Res, vol. 40, pp. 311-314, 19.05.2008 2008.

  • A. Ciucci, D. Meco, I. De Stefano, D. Travaglia, G. F. Zannoni, G. Scambia, R. Riccardi, A. Saran, M. Mancuso, and D. Gallo, "Gender effect in experimental models of human medulloblastoma: does the estrogen receptor β signaling play a role?," PLoS ONE, vol. 9, p. e101623, 2014.

  • R. Chu, A. van Hasselt, A. C. Vlantis, E. K. W. Ng, S. Y. W. Liu, M. D. Fan, S. K. Ng, A. B. W. Chan, Z. Liu, X.-y. Li, and G. G. Chen, "The cross-talk between estrogen receptor and peroxisome proliferatoractivated receptor gamma in thyroid cancer," Cancer, vol. 120, pp. 142-153, 2014.

  • E. Motylewska, O. Stasikowska, and G. MełeńMucha, "The inhibitory effect of diarylpropionitrile, a selective agonist of estrogen receptor beta, on the growth of MC38 colon cancer line," Cancer Lett, vol. 276, pp. 68-73, 2009.

  • S. Shalini, L. Dorstyn, S. Dawar, and S. Kumar, "Old, new and emerging functions of caspases," Cell Death Differ, vol. 22, pp. 526-539, 2015.

  • Y. Ji, S. Sun, S. Xia, L. Yang, X. Li, and L. Qi, "Short term high fat diet challenge promotes alternative macrophage polarization in adipose tissue via natural killer T cells and interleukin-4," J Biol Chem, vol. 287, pp. 24378-24386, July 13, 2012 2012.

  • V. Iansante, P. M. Choy, S. W. Fung, Y. Liu, J.-G. Chai, J. Dyson, A. Del Rio, C. D'Santos, R. Williams, S. Chokshi, R. A. Anders, C. Bubici, and S. Papa, "PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1dependent PKM2 phosphorylation and activation," Nat Commun, vol. 6, p. 7882, 2015.

  • P. E. Chappell and J. E. Levine, "Stimulation of gonadotropin-releasing hormone surges by estrogen. I. Role of hypothalamic progesterone receptors," Endocrinology, vol. 141, pp. 1477-1485, 2000/04/01 2000.

  • W. M. van Beurden-Lamers, A. O. Brinkmann, E. Mulder, and H. J. van der Molen, "High-affinity binding of oestradiol-17beta by cytosols from testis interstitial tissue, pituitary, adrenal, liver and accessory sex glands of the male rat," Biochem J, vol. 140, pp. 495-502, Jun 1974.

  • G. G. J. M. Kuiper, J. G. Lemmen, B. Carlsson, J. C. Corton, S. H. Safe, P. T. van der Saag, B. van der Burg, and J.-A. k. Gustafsson, "Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β," Endocrinology, vol. 139, pp. 4252-4263, 1998.

  • "Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome," Fertil Steril, vol. 81, pp. 19-25, 2004.

  • I. Hsu, C.-R. Yeh, S. Slavin, H. Miyamoto, G. J. Netto, M. Muyan, X.-R. Wu, E. M. Messing, E. A. Guancial, and S. Yeh, "Estrogen receptor alpha prevents bladder cancer via INPP4B inhibited akt pathway in vitro and in vivo," Oncotarget, vol. 5, pp. 7917-7935, 2014.

  • M. Marino, "Xenoestrogens challenge 17β-estradiol protective effects in colon cancer," World J Gastrointest Oncol, vol. 6, pp. 67-73, 2014.

  • J. Russo and I. H. Russo, "The role of estrogen in the initiation of breast cancer," J Steroid Biochem Mol Biol, vol. 102, pp. 89-96, 2006.

  • P. Argente-Arizón, A. Freire-Regatillo, J. Argente, and J. A. Chowen, "Role of non-neuronal cells in body weight and appetite control," Front Endocrinol (Lausanne), vol. 6, 2015-March-26 2015.

  • W. Komyod, M. Böhm, D. Metze, P. C. Heinrich, and I. Behrmann, "Constitutive suppressor of cytokine signaling 3 expression confers a growth advantage to a human melanoma cell line," Mol Cancer Res, vol. 5, pp. 271-281, 2007.

  • Y. Matsuda and T. Ichida, "p16 and p27 are functionally correlated during the progress of hepatocarcinogenesis," Med Mol Morphol, vol. 39, pp. 169-175, 2006.


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  • Effects of Estrogen and Estrogen Receptors on Glucose Metabolism of Liver Cancer Cell

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Authors

Minqian Shen
Structural Biology Miami University, Oxford, Ohio, United States
Haifei Shi
Department of Biology, Miami University Oxford, Ohio, United States

Abstract


Epidemiology data show that men have a much higher incidence of hepatocellular carcinoma (HCC) than women, suggesting that estrogen and its receptors may inhibit HCC development and progression. To investigate the potential inhibitory mechanisms of estrogens on HCC development, human cancer cell line HepG2 was treated with different concentrations of estrogen and specific agonists for estrogen receptor (ER) ERα and ERβ to determine the roles of estrogen and its receptors in HepG2 cancer cell proliferation, apoptosis, gene expression, and metabolic pathways. Our findings indicated that estrogen and its receptors suppressed HepG2 cell growth by inhibiting cell proliferation and stimulating cell apoptosis via primary activation of ERβ, and by affecting HepG2 glucose metabolism via primary activation of ERα. Identifying roles of different estrogen receptors would provide comprehensive understanding of estrogenic mechanisms in HCC development and shed light on potential treatments for HCC patients.

Keywords


HepG2, Estradiol, ERα, ERβ, Glycolysis, Oxidative Phosphorylation.

References