Effect of β-estradiol on the expression of human MGMT gene in cells in vitro

DOI: https://doi.org/10.7124/FEEO.v31.1496
Keywords: O(6)-methylguanine-DNA methyltransferase (MGMT), steroid hormones, β-estradiol, alkylating chemotherapy

Abstract

To determine whether the steroid hormone β-estradiol affects the transcription of the human MGMT gene. The expression status of the DNA repair enzyme O (6)-methylguanine-DNA methyltransferase (MGMT) is important when planning the treatment of patients with oncology, because its presence in tumor cells may reduce the effectiveness of alkylating chemotherapy. Alkylating chemotherapy is combined with hormone therapy in the treatment of tumors, so the study of the effect of β-estradiol on the number of transcripts of the human MGMT gene in cells in vitro has not only theoretical and also practical significance. Methods. We used a variety of methods, including culture, molecular genetic and biochemical, such as RNA isolation, cDNA synthesis, reverse transcriptase PCR, agarose and polyacrylamide gel electrophoresis, and statistical processing of the results. Results. We found a tendency of β-estradiol to downregulate the MGMT gene at mRNA level in both HEp-2 and 293 cells in a range of concentrations, except concentrations 1 and 5 nmol/L of β-estradiol in 293 cells. Conclusions. Our data support the hypothesis that β-estradiol is one of the hormonal regulators of the MGMT gene.

References

Verbeek B., Southgate T.D., Gilham D.E., Margison G.P. O6-Methylguanine-DNA methyltransferase inactivation and chemo-therapy. Br Med Bull. 2008. Vol. 85 (1). Р. 17–33. doi: 10.1093/bmb/ldm036.

Nakaz MOZ Ukrainy pro zatverdzhennia protokoliv nadannia medychnoi dopomohy za spetsialnistiu «onkolohiia» No. 554 vid 17.09.2007. URL: https://zakon.rada.gov.ua/rada/show/v0554282-07#Text (15.10.2020).

Schiavon G., Smith I.E. Status of adjuvant endocrine therapy for breast cancer. Breast Cancer Res. 2014. Vol. 16 (2). P. 206–222. doi: 10.1186/bcr3636.

Heldring N., Pike A., Andersson S., Matthews J., Cheng G., Hartman J., Tujague M., Ström A., Treuter E., Warner M., Gus-tafsson J.A. Estrogen receptors: how do they signal and what are their targets. Physiol. Rev. 2007. Vol. 87 (3). P. 905–931. doi: 10.1152/physrev.00026.2006.

Biswas T., Ramana C.V., Srinivasan G., Boldogh I., Hazra T.K., Chen Z., Tano K., Thompson E.B., Mitra S. Activation of human O6-methylguanine-DNA methyltransferase gene by glucocorticoid hormone. Oncogene. 1999. Vol. 18 (2). P. 525–532.

Ueda S., Mineta T., Nakahara Y., Okamoto H., Shiraishi T., Tabuchi K. Induction of the DNA repair gene O6-methylguanine-DNA methyltransferase by dexamethasone in glioblastomas. J Neurosurg. 2004. Vol. 101 (4). P. 659–663. doi: 10.3171/jns.2004.101.4.0659.

Nidoieva Z.M., Samoilenko І.О., Pidpala O.V., Lukash L.L., Iatsyshyna A.P. Bioinformatic search of hormone response ele-ments within the human O6-methylguanine-DNA methyltransferase (MGMT) gene promoter. Factors in Experimental Evolution of Organisms. 2015. Vol. 17. P. 74–78. [in Ukrainian]

Chang C., McDonnell D. P. Molecular pathways: the metabolic regulator estrogen-related receptor α as a therapeutic target in cancer. Clin. Cancer Res. 2012. Vol. 18 (22). P. 6089–6095. doi: 10.1158/1078-0432.CCR-11-3221.

Vrtačnik P., Ostanek B., Mencej-Bedrač S., Marc J. The many faces of estrogen signaling. Biochem. medica. 2014. Vol. 24 (3). P. 329–42. doi: 10.11613/BM.2014.035.

Santen R., Cavalieri E., Rogan E., Russo J., Guttenplan J., Ingle J., Yue W. Estrogen mediation of breast tumor formation in-volves estrogen receptor-dependent, as well as independent, genotoxic effects. Ann. N. Y. Acad. Sci. 2009. Vol. 1155. P. 132–140. doi: 10.1111/j.1749-6632.2008.03685.x18.

Hammond G. L. Diverse roles for sex hormone-binding globulin in reproduction. Biol. Reprod. 2011. Vol. 85 (3). P. 431–41. doi: 10.1095/biolreprod.111.092593.

Roseff S. J., Bangah M. L., Kettel L. M., Vale W., Rivier J., Burger H. G., Yen S. S. Dynamic changes in circulating inhibin levels during the luteal-follicular transition of the human menstrual cycle. J. Clin. Endocrinol. Metab. 1989. Vol. 69 (5). P. 1033–1039. doi: 10.1210/jcem-69-5-1033.

Nakajima Y., Osakabe A., Waku T., Suzuki T., Akaogi K., Fujimura T., Homma Y., Inoue S., Yanagisawa J. Estrogen exhibits a biphasic effect on prostate tumor growth through the ERβ-KLF5 pathway. Ml. Cell. Biol. 2015. Vol. 19 (36). P. 144–156. doi: 10.1128/MCB.00625-15.

Mak P., Li J., Samanta S., Mercurio A. M. ERβ regulation of NF-kB activation in prostate cancer is mediated by HIF-1. Onco-target. 2015. Vol. 6 (37). P. 40247–40254. doi: 10.18632/oncotarget.5377.

Mungenast F., Thalhammer T. Estrogen biosynthesis and action in ovarian cancer. Front. Endocrinol. (Lausanne). 2014. Vol. 5. P. 192. doi: 10.3389/fendo.2014.00192.