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The Anti-Proliferative Effect of Genistein on Antioxidant System, Cell Proliferation, and Apoptosis: Implications for Hormone- Refractory Prostate Cancer Therapy

Year 2025, Volume: 78 Issue: 1, 27 - 32, 31.03.2025

Abstract

Objectives: This study aims to examine the effect of different genistein concentrations on apoptosis, estrogen receptor beta, and manganese superoxide dismutase (MnSOD) protein expressions in PC3 hormone-resistant metastatic prostate cancer cell lines.

Materials and Methods: Genistein concentrations of 0, 0.01, 0.1, 0.5, 1, 5, 10, and and 50 μM were applied to PC3 hormone-resistant metastatic prostate cancer cell lines for 48 hours and water soluble tetrazolium salt-1 cell proliferation assay was performed. Protein was extracted from the cells and cleaved poly (ADP-ribose) polymerase, estrogen receptor beta (ERβ), and MnSOD protein expression levels were examined using the Western blot protocol. One-way analysis of variance (ANOVA) and Student’s t-test statistical analysis methods were applied to determine whether there are statistically significant differences.

Results: Genistein was found to change ERβ expression in PC3 cells depending on concentration. While ERβ protein expression increases observed at low concentrations (0.01-0.5 μM), it sometimes decreased to baseline or increased modestly at high concentrations (1-50 μM). MnSOD protein expression showed a stimulating effect on the protein expression level at high concentrations (1-50 μM).

Conclusion: This research study investigates how different concentrations of genistein affect cell proliferation, apoptosis, estrogen receptor beta, and MnSOD protein expression levels in PC3 hormone-refractory prostate cancer cells.

Ethical Statement

Ethics Committee Approval: The cells used in the study are commercially available, so ethics committee approval is not required.

Supporting Institution

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Project Number

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Thanks

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References

  • 1. Carlsson SV, Vickers AJ. Screening for prostate cancer. Med Clin North Am. 2020;104:1051-1062.
  • 2. Feldman B, Feldman D. The development of androgen-independent prostate cancer. Nat Rev Cancer. 2001;1:34-45.
  • 3. Macedo-Silva C, Benedetti R, Ciardiello F, et al. Epigenetic mechanisms underlying prostate cancer radioresistance. Clin Epigenet. 2021;13:125.
  • 4. Ramírez-de-Arellano A, Pereira-Suárez AL, Rico-Fuentes C, et al. Distribution and effects of estrogen receptors in prostate cancer: associated molecular mechanisms. Front Endocrinol (Lausanne). 2022;12:811578.
  • 5. Spagnuolo C, Russo GL, Bilotto S, et al. Genistein and cancer: current status, challenges, and future directions. Advances in Nutrition. 2015;6:408-419.
  • 6. Li Y, Ahmed F, Ali S, et al. Inactivation of nuclear factor kappaB by soy isoflavone genistein contributes to increased apoptosis induced by chemotherapeutic agents in human cancer cells. Cancer Research. 2005;65:6934-6942.
  • 7. Tuli HS, Tuorkey MJ, Thakral F, et al. Molecular mechanisms of action of genistein in cancer: recent advances. Front Pharmacol. 2019;10:1336.
  • 8. Di Zazzo E, Galasso G, Giovannelli P, et al. Estrogens and their receptors in prostate cancer: therapeutic implications. Front Oncol. 2018;8:2.
  • 9. Sharifi-Rad J, Quispe C, Imran M, et. al. Genistein: an integrative overview of its mode of action, pharmacological properties, and health benefits. Oxid Med Cell Longev. 2021;2021:3268136.
  • 10. Liu M, Sun X, Chen B, et. al. Insights into manganese superoxide dismutase and human diseases. Int J Mol Sci. 2022;23:15893.
  • 11. Ekoue DN, He C, Diamond AM, et al. Manganese superoxide dismutase and glutathione peroxidase-1 contribute to the rise and fall of mitochondrial reactive oxygen species which drive oncogenesis. Biochimica et Biophysica Acta (BBA)-Bioenergetics. 2017;1858:628-632.
  • 12. Park CE, Yun H, Lee EB, et. al. The antioxidant effects of genistein are associated with AMP-activated protein kinase activation and PTEN induction in prostate cancer cells. J Med Food. 2010;13:815-820.
  • 13. El Touny LH, and Banerjee PP. Akt GSK‐3 pathway as a target in genisteininduced inhibition of TRAMP prostate cancer progression toward a poorly differentiated phenotype. Carcinogenesis. 2007;28:1710-1717.
  • 14. Touny LH, and Banerjee PP. Identification of a biphasic role for genistein in the regulation of prostate cancer growth and metastasis. Cancer Research. 2009;69:3695-3703.
  • 15. Harper CE, Cook LM, Patel BB, et al. Genistein and resveratrol, alone and in combination, suppress prostate cancer in SV‐40 tag rats. Prostate. 2009;69:1668-1682.
  • 16. Terzioglu-Usak S, Yildiz MT, Goncu B, et. al. Achieving the balance: biphasic effects of genistein on PC-3 cells. J Food Biochem. 2019;43:e12951.
  • 17. Li Y, Bhuiyan M, Sarkar FH. Induction of apoptosis and inhibition of c-erbB-2 in MDA-MB-435 cells by genistein. Int J Oncol. 1999;15:525-533.
  • 18. Zhang LL, Li L, Wu DP, et al. A novel anti-cancer effect of genistein: reversal of epithelial mesenchymal transition in prostate cancer cells. Acta Pharmacol Sin. 2008;29:1060-1068.
  • 19. Lynch SM, O’Neill KM, McKenna MM, et al. Regulation of miR-200c and miR-141 by methylation in prostate cancer. Prostate. 2016;76:1146-1159.
  • 20. Asgari M, Morakabati A. Estrogen receptor beta expression in prostate adenocarcinoma. Diagn Pathol. 2011;6:61.
  • 21. Christoforou P, Christopoulos PF, Koutsilieris M. The role of estrogen receptor β in prostate cancer. Mol Med. 2014;20:427-434.
  • 22. Piccolella M, Crippa V, Messi E, et al. Modulators of estrogen receptor inhibit proliferation and migration of prostate cancer cells. Pharmacol Res. 2014;79:13-20.
  • 23. Ji X, Liu K, Li Q, et. al. A mini-review of flavone isomers apigenin and genistein in prostate cancer treatment. Front Pharmacol. 2022;13:851589.
  • 24. Aydın YM, Şahin AB, Dölek R, et al. Prognostic value of estrogen receptors in patients who underwent prostatectomy for nonmetastatic prostate cancer. Oncol Lett. 2023;25:78.
  • 25. Yan L, Spitznagel EL. Soy consumption and prostate cancer risk in men: a revisit of a meta-analysis. Am J Clin Nutr. 2009;89:1155-1163.
  • 26. Zhang Y, Liu D, Wang Y. Genistein induces G2/M cell cycle arrest and apoptosis of human prostate cancer cells via activation of ATM/ATRChk1/ 2-Cdc25C pathway. Phytomedicine. 2015;22:885-894.
  • 27. Borrás C, Gambini J, Gómez-Cabrera MC, et al. Genistein, a soy isoflavone, up-regulates expression of antioxidant genes: involvement of estrogen receptors, ERK1/2, and NFkappaB. FASEB J. 2006;20:2136-2138.
  • 28. Gian Luigi Russo. Ins and outs of dietary phytochemicals in cancer chemoprevention. Biochemical Pharmacology. 2007;74:533-544.
  • 29. Van der Eecken H, Joniau S, Berghen C, et al. The use of soy isoflavones in the treatment of prostate cancer: a focus on the cellular effects. Nutrients. 2023;15:4856.

Genisteinin Antioksidan Sistem, Hücre Çoğalması ve Apoptoz Üzerindeki Anti-Proliferatif Etkisi: Hormon Refrakter Prostat Kanser Tedavisinde Uygulamalar

Year 2025, Volume: 78 Issue: 1, 27 - 32, 31.03.2025

Abstract

Amaç: Bu çalışmanın amacı hormona dirençli olan PC3 metastatik prostat kanser hücre serilerinde farklı genistein konsantrasyonlarının apoptoz, östrojen reseptör beta ve manganez süperoksit dismutaz (MnSOD) protein ekspresyonlarındaki etkisini incelemektir.

Gereç ve Yöntem: PC3 hormona dirençli olan metastatik prostat kanser hücre serilerine 0, 0,01, 0,1, 0,5, 1, 5, 10, 50 μM genistein konsantrasyonları 48 saat uygulanmıştır ve suda çözünebilen tetrazolyum tuzu-1 hücre proliferasyon yöntemi uygulanmıştır. Hücrelerden protein ekstrekte edilip, Western blot yöntemi kullanılarak cleaved poli (ADP-riboz) polimeraz, östrojen reseptörü beta (ERβ) ve MnSOD protein ekspresyon seviyeleri incelenmiştir. Tek yönlü varyans analizi (ANOVA) ve Student’s t-test istatistiksel analiz metodları uygulanmıştır.

Bulgular: Genistein PC3 hücrelerinde konsantrasyona bağlı olarak ERβ ekspresyonunu değiştirdiği saptanmıştır. Düşük konsantrasyonlarda (0,01-0,5 μM) ERβ protein ekspresyonu artarken, yüksek konsantrasyonlarda (1-50 μM) bazen temel seviyeye düşerek ya da ılımlı artarak farklılık göstermiştir. MnSOD protein ekspresyonu ise yüksek konsantrasyonlarda (1-50 μM) protein ekspresyon seviyesi üzerinde uyarıcı etki göstermiştir.

Ethical Statement

-

Supporting Institution

-

Project Number

-

Thanks

-

References

  • 1. Carlsson SV, Vickers AJ. Screening for prostate cancer. Med Clin North Am. 2020;104:1051-1062.
  • 2. Feldman B, Feldman D. The development of androgen-independent prostate cancer. Nat Rev Cancer. 2001;1:34-45.
  • 3. Macedo-Silva C, Benedetti R, Ciardiello F, et al. Epigenetic mechanisms underlying prostate cancer radioresistance. Clin Epigenet. 2021;13:125.
  • 4. Ramírez-de-Arellano A, Pereira-Suárez AL, Rico-Fuentes C, et al. Distribution and effects of estrogen receptors in prostate cancer: associated molecular mechanisms. Front Endocrinol (Lausanne). 2022;12:811578.
  • 5. Spagnuolo C, Russo GL, Bilotto S, et al. Genistein and cancer: current status, challenges, and future directions. Advances in Nutrition. 2015;6:408-419.
  • 6. Li Y, Ahmed F, Ali S, et al. Inactivation of nuclear factor kappaB by soy isoflavone genistein contributes to increased apoptosis induced by chemotherapeutic agents in human cancer cells. Cancer Research. 2005;65:6934-6942.
  • 7. Tuli HS, Tuorkey MJ, Thakral F, et al. Molecular mechanisms of action of genistein in cancer: recent advances. Front Pharmacol. 2019;10:1336.
  • 8. Di Zazzo E, Galasso G, Giovannelli P, et al. Estrogens and their receptors in prostate cancer: therapeutic implications. Front Oncol. 2018;8:2.
  • 9. Sharifi-Rad J, Quispe C, Imran M, et. al. Genistein: an integrative overview of its mode of action, pharmacological properties, and health benefits. Oxid Med Cell Longev. 2021;2021:3268136.
  • 10. Liu M, Sun X, Chen B, et. al. Insights into manganese superoxide dismutase and human diseases. Int J Mol Sci. 2022;23:15893.
  • 11. Ekoue DN, He C, Diamond AM, et al. Manganese superoxide dismutase and glutathione peroxidase-1 contribute to the rise and fall of mitochondrial reactive oxygen species which drive oncogenesis. Biochimica et Biophysica Acta (BBA)-Bioenergetics. 2017;1858:628-632.
  • 12. Park CE, Yun H, Lee EB, et. al. The antioxidant effects of genistein are associated with AMP-activated protein kinase activation and PTEN induction in prostate cancer cells. J Med Food. 2010;13:815-820.
  • 13. El Touny LH, and Banerjee PP. Akt GSK‐3 pathway as a target in genisteininduced inhibition of TRAMP prostate cancer progression toward a poorly differentiated phenotype. Carcinogenesis. 2007;28:1710-1717.
  • 14. Touny LH, and Banerjee PP. Identification of a biphasic role for genistein in the regulation of prostate cancer growth and metastasis. Cancer Research. 2009;69:3695-3703.
  • 15. Harper CE, Cook LM, Patel BB, et al. Genistein and resveratrol, alone and in combination, suppress prostate cancer in SV‐40 tag rats. Prostate. 2009;69:1668-1682.
  • 16. Terzioglu-Usak S, Yildiz MT, Goncu B, et. al. Achieving the balance: biphasic effects of genistein on PC-3 cells. J Food Biochem. 2019;43:e12951.
  • 17. Li Y, Bhuiyan M, Sarkar FH. Induction of apoptosis and inhibition of c-erbB-2 in MDA-MB-435 cells by genistein. Int J Oncol. 1999;15:525-533.
  • 18. Zhang LL, Li L, Wu DP, et al. A novel anti-cancer effect of genistein: reversal of epithelial mesenchymal transition in prostate cancer cells. Acta Pharmacol Sin. 2008;29:1060-1068.
  • 19. Lynch SM, O’Neill KM, McKenna MM, et al. Regulation of miR-200c and miR-141 by methylation in prostate cancer. Prostate. 2016;76:1146-1159.
  • 20. Asgari M, Morakabati A. Estrogen receptor beta expression in prostate adenocarcinoma. Diagn Pathol. 2011;6:61.
  • 21. Christoforou P, Christopoulos PF, Koutsilieris M. The role of estrogen receptor β in prostate cancer. Mol Med. 2014;20:427-434.
  • 22. Piccolella M, Crippa V, Messi E, et al. Modulators of estrogen receptor inhibit proliferation and migration of prostate cancer cells. Pharmacol Res. 2014;79:13-20.
  • 23. Ji X, Liu K, Li Q, et. al. A mini-review of flavone isomers apigenin and genistein in prostate cancer treatment. Front Pharmacol. 2022;13:851589.
  • 24. Aydın YM, Şahin AB, Dölek R, et al. Prognostic value of estrogen receptors in patients who underwent prostatectomy for nonmetastatic prostate cancer. Oncol Lett. 2023;25:78.
  • 25. Yan L, Spitznagel EL. Soy consumption and prostate cancer risk in men: a revisit of a meta-analysis. Am J Clin Nutr. 2009;89:1155-1163.
  • 26. Zhang Y, Liu D, Wang Y. Genistein induces G2/M cell cycle arrest and apoptosis of human prostate cancer cells via activation of ATM/ATRChk1/ 2-Cdc25C pathway. Phytomedicine. 2015;22:885-894.
  • 27. Borrás C, Gambini J, Gómez-Cabrera MC, et al. Genistein, a soy isoflavone, up-regulates expression of antioxidant genes: involvement of estrogen receptors, ERK1/2, and NFkappaB. FASEB J. 2006;20:2136-2138.
  • 28. Gian Luigi Russo. Ins and outs of dietary phytochemicals in cancer chemoprevention. Biochemical Pharmacology. 2007;74:533-544.
  • 29. Van der Eecken H, Joniau S, Berghen C, et al. The use of soy isoflavones in the treatment of prostate cancer: a focus on the cellular effects. Nutrients. 2023;15:4856.
There are 29 citations in total.

Details

Primary Language English
Subjects Pharmaceutical Toxicology
Journal Section Research Article
Authors

Nur Ozten Kandas 0000-0002-0441-8397

Project Number -
Submission Date July 24, 2024
Acceptance Date January 23, 2025
Publication Date March 31, 2025
Published in Issue Year 2025 Volume: 78 Issue: 1

Cite

APA Ozten Kandas, N. (2025). The Anti-Proliferative Effect of Genistein on Antioxidant System, Cell Proliferation, and Apoptosis: Implications for Hormone- Refractory Prostate Cancer Therapy. Ankara Üniversitesi Tıp Fakültesi Mecmuası, 78(1), 27-32.
AMA Ozten Kandas N. The Anti-Proliferative Effect of Genistein on Antioxidant System, Cell Proliferation, and Apoptosis: Implications for Hormone- Refractory Prostate Cancer Therapy. Ankara Üniversitesi Tıp Fakültesi Mecmuası. March 2025;78(1):27-32.
Chicago Ozten Kandas, Nur. “The Anti-Proliferative Effect of Genistein on Antioxidant System, Cell Proliferation, and Apoptosis: Implications for Hormone- Refractory Prostate Cancer Therapy”. Ankara Üniversitesi Tıp Fakültesi Mecmuası 78, no. 1 (March 2025): 27-32.
EndNote Ozten Kandas N (March 1, 2025) The Anti-Proliferative Effect of Genistein on Antioxidant System, Cell Proliferation, and Apoptosis: Implications for Hormone- Refractory Prostate Cancer Therapy. Ankara Üniversitesi Tıp Fakültesi Mecmuası 78 1 27–32.
IEEE N. Ozten Kandas, “The Anti-Proliferative Effect of Genistein on Antioxidant System, Cell Proliferation, and Apoptosis: Implications for Hormone- Refractory Prostate Cancer Therapy”, Ankara Üniversitesi Tıp Fakültesi Mecmuası, vol. 78, no. 1, pp. 27–32, 2025.
ISNAD Ozten Kandas, Nur. “The Anti-Proliferative Effect of Genistein on Antioxidant System, Cell Proliferation, and Apoptosis: Implications for Hormone- Refractory Prostate Cancer Therapy”. Ankara Üniversitesi Tıp Fakültesi Mecmuası 78/1 (March2025), 27-32.
JAMA Ozten Kandas N. The Anti-Proliferative Effect of Genistein on Antioxidant System, Cell Proliferation, and Apoptosis: Implications for Hormone- Refractory Prostate Cancer Therapy. Ankara Üniversitesi Tıp Fakültesi Mecmuası. 2025;78:27–32.
MLA Ozten Kandas, Nur. “The Anti-Proliferative Effect of Genistein on Antioxidant System, Cell Proliferation, and Apoptosis: Implications for Hormone- Refractory Prostate Cancer Therapy”. Ankara Üniversitesi Tıp Fakültesi Mecmuası, vol. 78, no. 1, 2025, pp. 27-32.
Vancouver Ozten Kandas N. The Anti-Proliferative Effect of Genistein on Antioxidant System, Cell Proliferation, and Apoptosis: Implications for Hormone- Refractory Prostate Cancer Therapy. Ankara Üniversitesi Tıp Fakültesi Mecmuası. 2025;78(1):27-32.