Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Resveratrol Inhibits IL-6-Induced Transcriptional Activity of AR and STAT3 in Human Prostate Cancer LNCaP-FGC Cells

  • Lee, Mee-Hyun (Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University) ;
  • Kundu, Joydeb Kumar (College of Pharmacy, Keimyung University) ;
  • Keum, Young-Sam (College of Pharmacy, Dongguk University) ;
  • Cho, Yong-Yeon (College of Pharmacy, The Catholic University of Korea) ;
  • Surh, Young-Joon (Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University) ;
  • Choi, Bu Young (Pharmaceutical Science and Engineering, School of Convergence Bioscience and Technology, Seowon University)
  • Received : 2014.05.27
  • Accepted : 2014.06.24
  • Published : 2014.09.30
Download PDF
⟨ Previous Next ⟩

Abstract

Prostate cancer is the most frequently diagnosed cancer. Although prostate tumors respond to androgen ablation therapy at an early stage, they often acquire the potential of androgen-independent growth. Elevated transcriptional activity of androgen receptor (AR) and/or signal transducer and activator of transcription-3 (STAT3) contributes to the proliferation of prostate cancer cells. In the present study, we examined the effect of resveratrol, a phytoalexin present in grapes, on the reporter gene activity of AR and STAT3 in human prostate cancer (LNCaP-FGC) cells stimulated with interleukin-6 (IL-6) and/or dihydrotestosterone (DHT). Our study revealed that resveratrol suppressed the growth of LNCaP-FGC cells in a time- and concentration-dependent manner. Whereas the AR transcriptional activity was induced by treatment with either IL-6 or DHT, the STAT3 transcriptional activity was induced only by treatment with IL-6 but not with DHT. Resveratrol significantly attenuated IL-6-induced STAT3 transcriptional activity, and DHT- or IL-6-induced AR transcriptional activity. Treatment of cells with DHT plus IL-6 significantly increased the AR transcriptional activity as compared to DHT or IL-6 treatment alone and resveratrol markedly diminished DHT plus IL-6-induced AR transcriptional activity. Furthermore, the production of prostate-specific antigen (PSA) was decreased by resveratrol in the DHT-, IL-6- or DHT plus IL-6-treated LNCaP-FGC cells. Taken together, the inhibitory effects of resveratrol on IL-6- and/or DHT-induced AR transcriptional activity in LNCaP prostate cancer cells are partly mediated through the suppression of STAT3 reporter gene activity, suggesting that resveratrol may be a promising therapeutic choice for the treatment of prostate cancer.

Keywords

References

  1. Bommareddy, A., Eggleston, W., Prelewicz, S., Antal, A., Witczak, Z., McCune, D. F. and Vanwert, A. L. (2013) Chemoprevention of prostate cancer by major dietary phytochemicals. Anticancer Res. 33, 4163-4174.
  2. Chun, J. Y., Nadiminty, N., Dutt, S., Lou, W., Yang, J. C., Kung, H. J., Evans, C. P. and Gao, A. C. (2009) Interleukin-6 regulates androgen synthesis in prostate cancer cells. Clin. Cancer Res. 15, 4815-4822. https://doi.org/10.1158/1078-0432.CCR-09-0640
  3. Guo, Y., Xu, F., Lu, T., Duan, Z. and Zhang, Z. (2012) Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer Treat. Rev. 38, 904-910. https://doi.org/10.1016/j.ctrv.2012.04.007
  4. Ha, S., Iqbal, N. J., Mita, P., Ruoff, R., Gerald, W. L., Lepor, H., Taneja, S. S., Lee, P., Melamed, J., Garabedian, M. J. and Logan, S. K. (2013) Phosphorylation of the androgen receptor by PIM1 in hormone refractory prostate cancer. Oncogene 32, 3992-4000. https://doi.org/10.1038/onc.2012.412
  5. Harada, N., Atarashi, K., Murata, Y., Yamaji, R., Nakano, Y. and Inui, H. (2011) Inhibitory mechanisms of the transcriptional activity of androgen receptor by resveratrol: Implication of DNA binding and acetylation of the receptor. J. Steroid Biochem. Mol. Biol. 123, 65-70. https://doi.org/10.1016/j.jsbmb.2010.11.002
  6. Harada, N., Murata, Y., Yamaji, R., Miura, T., Inui, H. and Nakano, Y. (2007) Resveratrol down-regulates the androgen receptor at the post-translational level in prostate cancer cells. J. Nutr. Sci. Vitaminol. (Tokyo) 53, 556-560. https://doi.org/10.3177/jnsv.53.556
  7. Kai, L. and Levenson, A. S. (2011) Combination of resveratrol and antiandrogen flutamide has synergistic effect on androgen receptor inhibition in prostate cancer cells. Anticancer Res. 31, 3323-3330.
  8. Kotha, A., Sekharam, M., Cilenti, L., Siddiquee, K., Khaled, A., Zervos, A. S., Carter, B., Turkson, J. and Jove, R. (2006) Resveratrol inhibits Src and Stat3 signaling and induces the apoptosis of malignant cells containing activated Stat3 protein. Mol. Cancer Ther. 5, 621-629. https://doi.org/10.1158/1535-7163.MCT-05-0268
  9. Kundu, J. K. and Surh, Y. J. (2008) Cancer chemopreventive and therapeutic potential of resveratrol: mechanistic perspectives. Cancer Lett. 269, 243-261. https://doi.org/10.1016/j.canlet.2008.03.057
  10. Laufer, M., Denmeade, S. R., Sinibaldi, V. J., Carducci, M. A. and Eisenberger, M. A. (2000) Complete androgen blockade for prostate cancer: what went wrong? J. Urol. 164, 3-9. https://doi.org/10.1016/S0022-5347(05)67436-8
  11. Mitchell, S. H., Zhu, W. and Young, C. Y. (1999) Resveratrol inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. Cancer Res. 59, 5892-5895.
  12. Narayanan, B. A., Narayanan, N. K., Re, G. G. and Nixon, D. W. (2003) Differential expression of genes induced by resveratrol in LNCaP cells: P53-mediated molecular targets. Int. J. Cancer 104, 204-212. https://doi.org/10.1002/ijc.10932
  13. Ratan, H. L., Steward, W. P., Gescher, A. J. and Mellon, J. K. (2002) Resveratrol--a prostate cancer chemopreventive agent? Urol. Oncol. 7, 223-227. https://doi.org/10.1016/S1078-1439(02)00194-1
  14. Shankar, S., Singh, G. and Srivastava, R. K. (2007) Chemoprevention by resveratrol: molecular mechanisms and therapeutic potential. Front. Biosci. 12, 4839-4854. https://doi.org/10.2741/2432
  15. Shi, W. F., Leong, M., Cho, E., Farrell, J., Chen, H. C., Tian, J. and Zhang, D. (2009) Repressive effects of resveratrol on androgen receptor transcriptional activity. PLoS One 4, e7398. https://doi.org/10.1371/journal.pone.0007398
  16. Siegel, R., Ma, J., Zou, Z. and Jemal, A. (2014) Cancer statistics, 2014. CA Cancer J. Clin. 64, 9-29. https://doi.org/10.3322/caac.21208
  17. van der Poel, H. G., Zevenhoven, J. and Bergman, A. M. (2010) Pim1 regulates androgen-dependent survival signaling in prostate cancer cells. Urol. Int. 84, 212-220. https://doi.org/10.1159/000277601
  18. Walsh, P. C., DeWeese, T. L. and Eisenberger, M. A. (2007). Clinical practice. Localized prostate cancer. N. Engl. J. Med. 357, 2696-2705. https://doi.org/10.1056/NEJMcp0706784
  19. Wang, Z., Fan, J., Liu, M., Yeung, S., Chang, A., Chow, M. S., Pon, D. and Huang, Y. (2013) Nutraceuticals for prostate cancer chemoprevention: from molecular mechanisms to clinical application. Expert Opin. Investig. Drugs 22, 1613-1626. https://doi.org/10.1517/13543784.2013.833183
  20. Zemskova, M., Sahakian, E., Bashkirova, S. and Lilly, M. (2008) The PIM1 kinase is a critical component of a survival pathway activated by docetaxel and promotes survival of docetaxel-treated prostate cancer cells. J. Biol. Chem. 283, 20635-20644. https://doi.org/10.1074/jbc.M709479200

Cited by

  1. Analysis of the intricate relationship between chronic inflammation and cancer vol.468, pp.1, 2015, https://doi.org/10.1042/BJ20141337
  2. Resveratrol in spermatogenesis vol.39, pp.7, 2015, https://doi.org/10.1002/cbin.10451
  3. Mechanisms of action of nonpeptide hormones on resveratrol-induced antiproliferation of cancer cells 2017, https://doi.org/10.1111/nyas.13423
  4. Resveratrol, piceatannol and analogs inhibit activation of both wild-type and T877A mutant androgen receptor 2017, https://doi.org/10.1016/j.jsbmb.2017.08.016
  5. Resveratrol as an anti-cancer agent: A review 2018, https://doi.org/10.1080/10408398.2016.1263597
  6. Withaferin-A Inhibits Colon Cancer Cell Growth by Blocking STAT3 Transcriptional Activity vol.20, pp.3, 2015, https://doi.org/10.15430/JCP.2015.20.3.185
  7. Targeting transcription factor STAT3 for cancer prevention and therapy vol.162, 2016, https://doi.org/10.1016/j.pharmthera.2015.10.004
  8. α-Viniferin activates autophagic apoptosis and cell death by reducing glucocorticoid receptor expression in castration-resistant prostate cancer cells vol.35, pp.7, 2014, https://doi.org/10.1007/s12032-018-1163-y
  9. Natural Compounds in Prostate Cancer Prevention and Treatment: Mechanisms of Action and Molecular Targets vol.9, pp.2, 2020, https://doi.org/10.3390/cells9020460
  10. Natural Product-Based Studies for the Management of Castration-Resistant Prostate Cancer: Computational to Clinical Studies vol.12, pp.None, 2021, https://doi.org/10.3389/fphar.2021.732266
  11. The Effects of Resveratrol on Prostate Cancer through Targeting the Tumor Microenvironment vol.11, pp.1, 2014, https://doi.org/10.3390/jox11010002
  12. The Role of Resveratrol in Human Male Fertility vol.26, pp.9, 2014, https://doi.org/10.3390/molecules26092495
  13. Molecular insights into phytochemicals‐driven break function in tumor microenvironment vol.45, pp.9, 2014, https://doi.org/10.1111/jfbc.13824
  14. Targeting Drug Chemo-Resistance in Cancer Using Natural Products vol.9, pp.10, 2014, https://doi.org/10.3390/biomedicines9101353