The Apoptotic Effects of Testosterone on Lung Cancer (A549) Cells
Subject Areas : Journal of Animal BiologyAzita Tishehyar 1 , Rahim Ahmadi 2 , Minoo Mahmoudi 3 , Abdolreza Mohamadnia 4
1 - Department of Biology, Hamadan Branch, Islamic Azad University, Hamadan, Iran
2 - Department of Biology, Hamadan Branch, Islamic Azad University, Hamadan, Iran
3 - Department of Biology, Hamadan Branch, Islamic Azad University, Hamadan, Iran
4 - Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
Keywords: Testosterone, Apoptosis, BAX, Lung Cancer, BCL2,
Abstract :
Studies have shown that sex steroids affect the proliferation of cancer cells at cellular and molecular levels. The present study investigated the apoptotic effects of testosterone on lung cancer (A549) cells in cell culture medium. In this experimental-laboratory study, the cytotoxic effects of testosterone on Hek293 and A549 cells were assayed using MTT method. Real time PCR was used to evaluate the expression levels of Bax and Bcl2 genes in A549 cells exposed to IC50 dose of testosterone. The data were statistically analyzed between groups using one-way ANOVA. Exposure of Hek293 and A549 cells to higher dose of testosterone (1000 microg/ml) of testosterone resulted in significant decrease in cell viability (P<0.001). IC50 dose of testosterone significantly decreased the anti-apoptotic Bcl-2 gene expression level (P<0.001) in A549 cells, however, did not significantly change the expression level of apoptotic Bax gene. The cytotoxic concentration of testosterone induces apoptosis in lung cancer cells by its inhibitory effect on anti-apoptotic Bcl-2 gene expression level. Accordingly, appropriate dose of testosterone has anti-cancer effects against lung cancer cells.
1. Anagnostopoulou V., Pediaditakis I., Alkahtani S., Alarifi S.A., Schmidt E.M., Lang F., Gravanis A., Charalampopoulos I., Stournaras C. 2013. Differential effects of dehydroepiandrosterone and testosterone in prostate and colon cancer cell apoptosis: the role of nerve growth factor (NGF) receptors. Endocrinology, 154(7): 2446-2456.
2. Bigdeli R., Shahnazari M., Panahnejad E., Cohan R.A., Dashbolaghi A., Asgary V. 2019. Cytotoxic and apoptotic properties of silver chloride nanoparticles synthesized using Escherichia coli cell-free supernatant on human breast cancer MCF 7 cell line. Artificial Cells, Nanomedicine, and Biotechnology, 47(1): 1603-1609.
3. Chávez-Riveros A., Garrido M., Apan M.T.R., Zambrano A., Díaz M., Bratoeff E. 2014. Synthesis and cytotoxic effect on cancer cell lines and macrophages of novel progesterone derivatives having an ester or a carbamate function at C-3 and C-17. European Journal of medicinal chemistry, 82: 498-505.
4. Corotchi M.C., Popa M.A., Simionescu M. 2016. Testosterone stimulates proliferation and preserves stemness of human adult mesenchymal stem cells and endothelial progenitor cells. Romanian Journal of Morphology and Embryology, 57(1): 75-80.
5. Farahmandlou N., Oryan S., Ahmadi R., Eydi A. 2019. The Effects of Cytotoxic Dose of Testosterone on Bax, Bcl2, and CD82/KAI1 Genes Expression in Colorectal Adenocarcinoma (HT29) and Brain Glioblastoma Cells (A172). Qom University of Medical Sciences Journal, 12(11): 1-9.
6. Finlay-Schultz J., Sartorius C.A. 2015. Steroid hormones, steroid receptors, and breast cancer stem cells. Journal of Mammary Gland Biology and Neoplasia, 20(1-2): 39-50.
7. Gholami N., Cohan R.A., Razavi A., Bigdeli R., Dashbolaghi A., Asgary V. 2020. Cytotoxic and apoptotic properties of a novel nano‐toxin formulation based on biologically synthesized silver nanoparticle loaded with recombinant truncated pseudomonas exotoxin A. Journal of Cellular Physiology, 235(4): 3711-3720.
8. Glaser R., Dimitrakakis C. 2015. Testosterone and breast cancer prevention. Maturitas, 82(3): 291-295.
9. Han B., Jiang P., Liu W., Xu H., Li Y., Li Z., Ma H., Yu Y., Li X., Ye X. 2018. Role of daucosterol linoleate on breast cancer: studies on apoptosis and metastasis. Journal of Agricultural and Food Chemistry, 66(24): 6031-6041.
10. Honda S., Loher P., Shigematsu M., Palazzo J.P., Suzuki R., Imoto I., Rigoutsos I., Kirino Y. 2015. Sex hormone-dependent tRNA halves enhance cell proliferation in breast and prostate cancers. Proceedings of the National Academy of Sciences, 112(29): E3816-E3825.
11. Kwak B., Mulhaupt F., Myit S., Mach F. 2000. Statins as a newly recognized type of Immunomodulator. Nature Medicine, 6(12): 1399-1402.
12. Li X., Zhang J., Zhu X., Wang P., Wang X., Li D. 2015. Progesterone reduces inflammation and apoptosis in neonatal rats with hypoxic ischemic brain damage through the PI3K/Akt pathway. International Journal of Clinical and Experimental Medicine, 8(5): 8197.
13. Ling S., Dai A., Williams M.R., Myles K., Dilley R.J., Komesaroff P.A., Sudhir K., 2002. Testosterone (T) enhances apoptosis-related damage in human vascular endothelial cells. Endocrinology, 143(3): 1119-1125.
14. Lopes R.A.M., Neves K.B., Pestana C.R., Queiroz A.L., Zanotto C.Z., Chignalia A.Z., Valim Y.M., Silveira L.R., Curti C., Tostes R.C., 2014. Testosterone induces apoptosis in vascular smooth muscle cells via extrinsic apoptotic pathway with mitochondria-generated reactive oxygen species involvement. American Journal of Physiology-Heart and Circulatory Physiology, 306(11): 1485-1494.
15. Molina J.R., Yang P., Cassivi S.D., Schild S.E., Adjei A.A. 2008, May. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. In Mayo Clinic Proceedings, 83(5): 584-594.
16. Patman G., 2015. Male hormones increase the incidence of colonic adenomas. Nature Reviews Gastroenterology and Hepatology, 12(1); 4-14.
17. Phillip M., Maor G., Assa S., Silbergeld A., Segev Y. 2001. Testosterone stimulates growth of tibial epiphyseal growth plate and insulin-like growth factor-1 receptor abundance in hypophysectomized and castrated rats. Endocrine, 16(1): 1-6.
18. Saxena A., Viswanathan S., Moshynska O., Tandon P., Sankaran K., Sheridan D.P., 2004. Mcl‐1 and Bcl‐2/Bax ratio are associated with treatment response but not with Rai stage in B cell chronic lymphocytic leukemia. American Journal of Hematology, 75(1): 22-33.
19. Torre L.A., Siegel R.L., Jemal A. 2016. Lung cancer statistics. Lung Lancer and Personalized Medicine, Springer, pp: 1-19.
20. Qrsted D.D., Nordestgaard B.G., Bojesen S.E. 2014. Plasma testosterone in the general population, cancer prognosis and cancer risk: a prospective cohort study. Annals of Oncology, 25(3): 712-718.
21. Verzola D., Gandolfo M.T., Salvatore F., Villaggio B., Gianiorio F., Traverso P., Deferrari G., Garibotto G., 2004. Testosterone promotes apoptotic damage in human renal tubular cells. Kidney International, 65(4): 1252-1261.
22. Warburton D., Hobaugh C., Wang G., Lin H., Wang R. 2015. Testosterone replacement therapy and the risk of prostate cancer. Asian Journal of Andrology, 17(6): 878-881.
23. Westphal D., Kluck R.M., Dewson G. 2014. Building blocks of the apoptotic pore: how Bax and Bak are activated and oligomerize during apoptosis. Cell Death and Differentiation, 21(2):196-205.
24. Wong M.C., Lao X.Q., Ho K.F., Goggins W.B., Shelly L.A. 2017. Incidence and mortality of lung cancer: global trends and association with socioeconomic status. Scientific Reports, 7(1): 1-9.
25. Yao Q., Wang W., Jin J., Min K., Yang J., Zhong Y., Xu C., Deng J., Zhou Y. 2018. Synergistic role of Caspase-8 and Caspase-3 expressions: Prognostic and predictive biomarkers in colorectal cancer. Cancer Biomarkers, 21(4): 899-908.
26. Yu X., Jiang Y., Wei W., Cong P., Ding Y., Xiang L., Wu K. 2015. Androgen receptor signaling regulates growth of glioblastoma multiforme in men. Tumor Biology, 36(2): 967-972.
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