The MODULATION OF GENES AND PROTEIN LOCALIZATION FOR ESTROGEN AND PROGESTERONE RECEPTORS IN CYCLOPHOSPHAMIDE-EFFECTED OVARY BY TOCOTRIENOLS SUPPLEMENTATION
Modulation of Genes and Protein Localization for Estrogen and Progesterone Receptors in Cyclophosphamide-effected Ovary by Tocotrienols Supplementation
DOI:
https://doi.org/10.22159/ajpcr.2019.v12i6.33448Keywords:
Estrogen receptor alpha,, Progesterone receptor,, Cyclophosphamide,, Infertility,, TocotrienolAbstract
Objective: The objective of the study was to investigate the role of tocotrienols (T3) in alteration and regulation of estrogen receptor (ER) and progesterone receptor (PR) genes and proteins expression that was hoped to explain the involvement of ER and PR signaling pathway as biomarker in maintaining fertility during chemotherapy treatment.
Methods: Fifty female ICR mice (10–12) weeks were equally divided into five groups: CPA, CPA and T3, normal saline, T3 only, and corn oil only. The treatment was given for 4 weeks and followed by super ovulation protocol application. Both ovaries were removed, RNA extraction and real-time quantitative polymerase chain reaction (PCR) were performed using the super green probe real-time PCR. Concentration of the forward, reverse primers involvement ER, PR, glyceraldehyde-ᴣ-phosphate dehydrogenase and α-actin genes. Histological processing was performed to apply IHC reactions using peroxidase for mouse biotinylated primary antibody.
Result: It was founded that significant downregulation of ERα gene was evident in the coadministration of CPA with T3 compared to CPA group (p<0.01). Meanwhile, highly significant expression of ERα gene in CPA-exposed ovary compared to the control group, which was by 5.9-fold (p<0.01). Moreover, the study revealed that CPA+ T3 is significantly reduced the protein localization of ER, PR in the ovary of CPA−exposed mice (p<0.05).
Conclusion: The results indicated that coadministration of T3 with CPA confers protection against altered genes and protein expression in ovaries. T3 may consider as a promising candidate for ovarian preservation due to chemotherapy-associated ER, PR genes, and protein overexpression.
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Salama M, Woodruff TK. Anticancer treatments and female fertility: Clinical concerns and role of oncologists in oncofertility practice. Expert Rev Anticancer Ther 2017;17:687-92.
Mungenast F, Thalhammer T. Estrogen biosynthesis and action in ovarian cancer. Front Endocrinol (Lausanne) 2014;5:192.
Chuffa LG, Lupi-Júnior LA, Costa AB, Amorim JP, Seiva FR. The role of sex hormones and steroid receptors on female reproductive cancers. Steroids 2017;118:93-108.
Hewitt SC, Korach KS. Estrogen receptors: New directions in the new millennium. Endocr Rev 2018;39:664-75.
Hui H, Hongying Z, Qing K, Yangfu J. Mechanisms for estrogen receptor expression in human cancer. Exp Hematol Oncol 2018;7:24.
Chang CY, McDonnell DP. Molecular pathways: The metabolic regulator estrogen-related receptor α as a therapeutic target in cancer. Clin Cancer Res 2012;18:6089-95.
Tomic D, Frech MS, Babus RK, Symonds D, Furth PA, Koos RD, et al. Effects of ERα-overexpressing on female reproduction in mice. Reprod Toxicol 2007;23:317-25.
Hamilton KJ, Arao Y, Korach KS. Estrogen hormone physiology: Reproductive findings from estrogen receptor mutant mice. Reprod Biol 2014;14:3-8.
Tomic D, Frech MS, Babus RK, Gupta RK, Furth PA, Koos PA, et al. Methoxychlor induces atresia of antral follicles in ERα-overexpressing mice. Toxicol Sci 2006;93:196-204.
Paulose T, Hannon PR, Peretz J, Craig ZR, Flaws JA. Estrogen receptor alpha overexpressing mouse antral follicles are sensitive to atresia induced by methoxychlor and its metabolites. Reprod Toxicol 2012;33:353-60.
Russell DL, Robker RL. Molecular mechanisms of ovulation: Co-ordination through the cumulus complex. Hum Reprod Update 2007;13:289-312.
Teilmann SC, Clement CA, Thorup J, Byskov AG, Christensen ST. Expression and localization of the progesterone receptor in mouse and human reproductive organs. J Endocrinol 2006;191:525-35.
Luo W, Gumen A, Haughian JM, Wiltbank MC. The role of luteinizing hormone in regulating gene expression during selection of a dominant follicle in cattle. Biol Reprod 2011;84:369-78.
Diep CH, Daniel AR, Mauro LJ, Knutson TP, Lange CA. Progesterone action in breast, uterine, and ovarian cancers. J Mol Endocrinol 2015;54:R31-53.
Louie MC, Sevigny MB. Steroid hormone receptors as prognostic markers in breast cancer. Am J Cancer Res 2017;7:1617-36.
Salvetti NR, Acosta JC, Gimeno EJ, Müller LA, Mazzini RA, Taboada AF, et al. Estrogen receptors alpha and beta and progesterone receptors in normal bovine ovarian follicles and cystic ovarian disease. Vet Pathol 2007;44:373-8.
Nakamura TJ, Sellix MT, Kudo T, Nakao N, Yoshimura T, Ebihara S, et al. Influence of the estrous cycle on clock gene expression in reproductive tissues: Effects of fluctuating ovarian steroid hormone levels. Steroids 2010;75:203-12.
Dysken MW, Sano M, Asthana S, Vertrees JE, Pallaki M, Llorente M, et al. Effect of vitamin E and memantine on functional decline in alzheimer disease: The TEAM-AD VA cooperative randomized trial. JAMA 2014;311:33-44.
Musalmah M, Hamiza SH, Nursiati MT, Yu J, Ping L, Zhang H, et al. Effects of aging and tocotrienol-rich fraction supplementation on brain arginine metabolism in rats. Oxid Med Cell Longev 2017;2017:13.
Mutalip SS, Ab-Rahim S, Rajikin MH. Vitamin E as an antioxidant in female reproductive health. Antioxidants (Basel) 2018;7:22.
Rajikin MH, Latif ES, Mar MR, Mat Top AG, Mokhtar NM. Deleterious effects of nicotine on the ultrastructure of oocytes: Role of gamma-tocotrienol. Med Sci Monit 2009;15:BR378-83.
Aggarwal BB, Sundaram C, Prasad S, Kannappan R. Tocotrienols, the Vitamin E of the 21st century: Its potential against cancer and other chronic diseases. Biochem Pharmacol 2010;80:1613-31.
Saleh HS, Omar E, Froemming GR, Said RM. Tocotrienol rich fraction supplementation confers protection on the ovary from cyclophosphamide induced ovary apoptosis. Asian Pac J Trop Dis 2014;4:234.
Thi TT, Yu MS, David KG. Antioxidants improve mouse preimplantation embryo development and viability. Hum Reprod 2016;31:1445-54.
Letterie GS. Anovulation in the prevention of cytotoxic induced follicular attrition and ovarian failure. Hum Reprod 2004;19:831-7.
Luo C, Zuñiga J, Edison E, Palla S, Dong W, Parker-Thornburg J, et al. Superovulation strategies for 6 commonly used mouse strains. J Am Assoc Lab Anim Sci 2011;50:471-8.
Durlej M, Tabarowski Z, Slomczynska M. Immunohistochemical study on differential distribution of progesterone receptor A and progesterone receptor B within the porcine ovary. Anim Reprod Sci 2010;121:167-73.
Burns KA, Korach KS. Estrogen receptors and human disease: An update. Arch Toxicol 2012;86:1491-504.
Iorga A, Cunningham CM, Moazeni S, Ruffenach G, Umar S, Eghbali M, et al. The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy. Biol Sex Differ 2017;8:33.
Vranic S, Gatalica Z, Deng H, Frkovic-Grazio S, Lee LM, Gurjeva O, et al. ER-α36, a novel isoform of ER-α66, is commonly over-expressed in apocrine and adenoid cystic carcinomas of the breast. J Clin Pathol 2011;64:54-7.
Shen Z, Luo H, Li S, Sheng B, Zhao M, Zhu H, et al. Correlation between estrogen receptor expression and prognosis in epithelial ovarian cancer: A meta-analysis. Oncotarget 2017;8:62400-13.
You H, Meng K, Wang ZY. The ER-α36/EGFR signaling loop promotes growth of hepatocellular carcinoma cells. Steroids 2018;134:78-87.
Danzo BJ. Environmental xenobiotics may disrupt normal endocrine function by interfering with the binding of physiological ligands to steroid receptors and binding proteins. Environ Health Perspect 1997;105:294-301.
Newbold RR, Jefferson WN, Padilla-Banks E. Long-term adverse effects of neonatal exposure to bisphenol A on the murine female reproductive tract. Reprod Toxicol 2007;24:253-8.
Matthews J, Gustafsson JA. Estrogen signaling: A subtle balance between ER alpha and ER beta. Mol Interv 2003;3:281-92.
Paulose T, Hernádez-Ochoa I, Basavarajappa MS, Peretz J, Flaws JA. Increased sensitivity of estrogen receptor alpha overexpressing antral follicles to methoxychlor and its metabolites. Toxicol Sci 2011;120:447-59.
Tannenbaum LV, Flaws JA. Exposure duration-dependent ovarian recovery in methoxychlor-treated mice. Birth Defects Res B Dev Reprod Toxicol 2015;104:238-43.
Kishk EA, Mohammed Ali MH. Effect of a gonadotropin-releasing hormone analogue on cyclophosphamide-induced ovarian toxicity in adult mice. Arch Gynecol Obstet 2013;287:1023-9.
Hazar SS, Al-Kayat ES. Modulation male fertility in diabetic rats by allicin administration. J Coll Educ Pure Sci 2017;7:96-110.
Chen XY, Xia HX, Guan HY, Li B, Zhang W. Follicle loss and apoptosis in cyclophosphamide-treated mice: What’s the matter? Int J Mol Sci 2016;17:836.
Fleisch MC, Chou YC, Cardiff RD, Asaithambi A, Shyamala G. Overexpression of progesterone receptor A isoform in mice leads to endometrial hyperproliferation, hyperplasia and atypia. Mol Hum Reprod 2009;15:241-9.
Maedeh M, Seyed JH, Saeed RM, Hamid YB, Ayat D, et al. Correlation between estrogen receptor expression and prognosis in epithelial ovarian cancer: A meta-analysis. Int J Reprod Biomed (Yazed) 2018;16:323-34.
Shyamala G, Yang X, Silberstein G, Barcellos-Hoff MH, Dale E. Transgenic mice carrying an imbalance in the native ratio of A to B forms of progesterone receptor exhibit developmental abnormalities in mammary glands. Proc Natl Acad Sci U S A 1998;95:696-701.
Graham JD, Yager ML, Hill HD, Asaithambi A, Shyamala G. Altered progesterone receptor isoform expression remodels progestin responsiveness of breast cancer cells. Mol Endocrinol 2005;19:2713-35.
Zhou H, Luo MP, Schönthal AH, Pike MC, Stallcup MR, Blumenthal M, et al. Effect of reproductive hormones on ovarian epithelial tumors: I. Effect on cell cycle activity. Cancer Biol Ther 2002;1:300-6.
Zhu X, Han Y, Fang Z, Wu W, Ji M, Teng F, et al. Progesterone protects ovarian cancer cells from cisplatin-induced inhibitory effects through progesterone receptor membrane component 1/2 as well as AKT signaling. Oncol Rep 2013;30:2488-94.
Akahira J, Inoue T, Suzuki T, Ito K, Konno R, Sato S, et al. Progesterone receptor isoforms A and B in human epithelial ovarian carcinoma: Immunohistochemical and RT-PCR studies. Br J Cancer 2000;83:1488-94.
Lenie S, Smitz J. Estrogen receptor subtypes localization shifts in cultured mouse ovarian follicles. Histochem Cell Biol 2008;129:827-40.
Leena RP, Khub CV, Madhavan GN. An immunohistochemical study on the expression of sex steroid receptors in canine mammary tumors. ISRN Vet Sci 2012;2012:7.
Ruijin S, Markstro E, Friberg PA, Maria J, Hakan B. Expression of progesterone receptor (PR) A and B isoforms in mouse granulosa cells: Stage-dependent PR- mediated regulation of apoptosis and cell proliferation. Biol Reprod 2003;68:914-21.
Chaddwick W, Zhou Y, Park SS, Wang L, Mitchell N. Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One 2010;5:e14352.
Barbati C, Pierdominici M, Gambardella L, Albedi FM, Karas R, Rosano G, et al. Cell surface estrogen receptor alpha is upregulated during subchronic metabolic stress and inhibits neuronal cell degeneration. PloS One 2012;7:e42339.
Ikeda K, Horie-Inoue K, Inoue S. Identification of estrogen-responsive genes based on the DNA binding properties of estrogen receptors using high-throughput sequencing technology. Acta Pharmacol Sin 2015;36:24-31.
Khallouki F, de Medina P, Caze-Subra S, Bystricky K, Balaguer P, Poirot M, et al. Molecular and biochemical analysis of the estrogenic and proliferative properties of vitamin E compounds. Front Oncol 2015;5:287.
Hewitt SC, Harrell JC, Korach KS. Lessons in estrogen biology from knockout and transgenic animals. Annu Rev Physiol 2005;67:285-308.
Mohammed H, Russell IA, Stark R, Rueda OM, Hickey TE, Tarulli GA, et al. Progesterone receptor modulates ERα action in breast cancer. Nature 2015;523:313-7.
Hurvitz SA, Pietras RJ. Rational management of endocrine resistance in breast cancer: A comprehensive review of estrogen receptor biology, treatment options, and future directions. Cancer 2008;113:2385-97.
Taylor S. A practical guide to publishing RT-PCR data that conform to the MIQE guidelines. Am Biotecnol Lab 2010;28:14.
Paterni I, Granchi C, Katzenellenbogen JA, Minutolo F. Estrogen receptors alpha (ERα) and beta (ERβ): Subtype-selective ligands and clinical potential. Steroids 2014;90:13-29.
Winneker RC, Fensome A, Zhang P, Yudt MR, McComas CC, Unwalla RJ, et al. A new generation of progesterone receptor modulators. Steroids 2008;73:689-701.
Aggarwal BB, Sundaram C, Prasad S, Kannappan R. Tocotrienols, the Vitamin E of the 21st century: Its potential against cancer and other chronic diseases. Biochem Pharmacol 2010;80:1613-31.
Subramani PC, Sasivarnam T, Krishnan G, Selvanathan I, Mani G, Ramasamy E, et al. Impact of geranoil on cyclophasphomide provoked cardiotoxic properties in vivo study. Int J Pharm Pharm Sci 2015;7:420-6.
Tarigan JB, Ginting M, Nainggolan FM. Synthesis and properties of new hydrogel from cross-linked galactomannan boric. J Phys 2018;1116:042041.
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