Skip to main content

Advertisement

SpringerLink
Log in

Pharmacological inhibition of androgen receptor expression induces cell death in prostate cancer cells

  • Original Article
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

The androgen receptor (AR) plays an important role in the pathogenesis and development of prostate cancer (PCa). Mostly, PCa progresses to androgen-independent PCa, which has activated AR signaling from androgen-dependent PCa. Thus, inhibition of AR signaling may be an important therapeutic target in androgen-dependent and castration-resistant PCa. In this study, we determined the anticancer effect of a newly found natural compound, sakurasosaponin (S-saponin), using androgen-dependent and castration-resistant PCa cell lines. S-saponin induces mitochondrial-mediated cell death in both androgen-dependent (LNCaP) and castration-resistant (22Rv1 and C4-2) PCa cells, via AR expression. S-saponin treatment induces a decrease in AR expression in a time- and dose-dependent manner and a potent decrease in the expression of its target genes, including prostate-specific antigen (PSA), transmembrane protease, serin 2 (TMPRSS2), and NK3 homeobox 1 (NKX3.1). Furthermore, S-saponin treatment decreases B-cell lymphoma-extra large (Bcl-xL) and mitochondrial membrane potential, thereby increasing the release of cytochrome c into the cytosol. Moreover, Bcl-xL inhibition and subsequent mitochondria-mediated cell death caused by S-saponin were reversed by Bcl-xL or AR overexpression. Interestingly, S-saponin-mediated cell death was significantly reduced by a reactive oxygen species (ROS) scavenger, N-acetylcystein. Animal xenograft experiments showed that S-saponin treatment significantly reduced tumor growth of AR-positive 22Rv1 xenografts but not AR-negative PC-3 xenografts. Taken together, for the first time, our results revealed that S-saponin induces mitochondrial-mediated cell death in androgen-dependent and castration-resistant cells through regulation of AR mechanisms, including downregulation of Bcl-xL expression and induction of ROS stress by decreasing mitochondrial membrane potential.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–386

    Article  CAS  PubMed  Google Scholar 

  2. Taitt HE (2018) Global trends and prostate cancer: a review of incidence, detection, and mortality as influenced by race, ethnicity, and geographic location. Am J Mens Health 12:(6):1807–1823

    Article  PubMed  PubMed Central  Google Scholar 

  3. Fujita K, Nonomura N (2018) Role of androgen receptor in prostate cancer: a review. World J Mens Health 10(36):180040

    Google Scholar 

  4. Massard C, Fizazi K Targeting continued androgen receptor signaling in prostate cancer. Clin Cancer Res 17(12):3876–3883

    Article  CAS  PubMed  Google Scholar 

  5. Tan MH, Li J, Xu HE, Melcher K, Yong EL (2015) Androgen receptor: structure, role in prostate cancer and drug discovery. Acta Pharmacol Sin 361:(1):3–23. https://doi.org/10.1371/journal.pgen.1006946

    Article  CAS  PubMed  Google Scholar 

  6. Isbarn H, Boccon-Gibod L, Carroll PR, Montorsi F, Schulman C, Smith MR, Sternberg CN, Studer UE (2009) Androgen deprivation therapy for the treatment of prostate cancer: consider both benefits and risks. Eur Urol 55(1):62–75

    Article  CAS  PubMed  Google Scholar 

  7. Cai Z, Chen W, Zhang J, Li H (2018) Androgen receptor: what we know and what we expect in castration-resistant prostate cancer. Int Urol Nephrol 50(10):1753–1764

    Article  CAS  PubMed  Google Scholar 

  8. Dong L, Zieren RC, Xue W, de Reijke TM, Pienta KJ (2019) Metastatic prostate cancer remains incurable, why? Asian J Urol 6(1):26–41

    Article  PubMed  Google Scholar 

  9. Watson PA, Arora VK, Sawyers CL (2015) Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat Rev Cancer 15(12):701–711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bluemn EG, Nelson PS (2012) The androgen/androgen receptor axis in prostate cancer. Curr Opin Oncol 24(3):251–257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Culig Z (2014) Targeting the androgen receptor in prostate cancer. Expert Opin Pharmacother 15(10):1427–1437

    Article  CAS  PubMed  Google Scholar 

  12. Nevedomskaya E, Baumgart SJ, Haendler B (2018) Recent advances in prostate cancer treatment and drug discovery. Int J Mol Sci 19(5):E1359

    Article  PubMed  Google Scholar 

  13. Ahmed A, Ali S, Sarkar FH (2014) Advances in androgen receptor targeted therapy for prostate cancer. J Cell Physiol 229(3):271–276

    Article  CAS  PubMed  Google Scholar 

  14. Chao DT, Korsmeyer SJ (1998) BCL-2 family: regulators of cell death. Annu Rev Immunol 16:395–419

    Article  CAS  PubMed  Google Scholar 

  15. Chan SL, Yu VC (2004) Proteins of the bcl-2 family in apoptosis signalling: from mechanistic insights to therapeutic opportunities. Clin Exp Pharmacol Physiol 31(3):119–128

    Article  CAS  PubMed  Google Scholar 

  16. Yamaguchi H, Wang HG (2002) Bcl-XL protects BimEL-induced Bax conformational change and cytochrome C release independent of interacting with Bax or BimEL. J Biol Chem 277(44):41604–41612

    Article  CAS  PubMed  Google Scholar 

  17. Sasazawa Y, Futamura Y, Tashiro E, Imoto M (2009) Vacuolar H+-ATPase inhibitors overcome Bcl-xL-mediated chemoresistance through restoration of a caspase-independent apoptotic pathway. Cancer Sci 100(8):1460–1467

    Article  CAS  PubMed  Google Scholar 

  18. Grad JM, Zeng XR, Boise LH (2000) Regulation of Bcl-xL: a little bit of this and a little bit of STAT. Curr Opin Oncol 12(6):543–549

    Article  CAS  PubMed  Google Scholar 

  19. Lebedeva I, Rando R, Ojwang J, Cossum P, Stein CA (2000) Bcl-xL in prostate cancer cells: effects of overexpression and down-regulation on chemosensitivity. Cancer Res 60(21):6052–6060

    CAS  PubMed  Google Scholar 

  20. Lin Y, Fukuchi J, Hiipakka RA, Kokontis JM, Xiang J (2007) Up-regulation of Bcl-2 is required for the progression of prostate cancer cells from an androgen-dependent to an androgen-independent growth stage. Cell Res 17(6):531–536

    Article  CAS  PubMed  Google Scholar 

  21. Castilla C, Congregado B, Chinchon D, Torrubia FJ, Japon MA, Saez C (2006) Bcl-xL is overexpressed in hormone-resistant prostate cancer and promotes survival of LNCaP cells via interaction with proapoptotic Bak. Endocrinology 147(10):4960–4967

    Article  CAS  PubMed  Google Scholar 

  22. Sun A, Tang J, Hong Y, Song J, Terranova PF, Thrasher JB, Svojanovsky S, Wang HG, Li B (2008) Androgen receptor-dependent regulation of Bcl-xL expression: Implication in prostate cancer progression. Prostate 68(4):453–461

    Article  CAS  PubMed  Google Scholar 

  23. Liao X, Tang S, Thrasher JB, Griebling TL, Li B (2005) Small-interfering RNA-induced androgen receptor silencing leads to apoptotic cell death in prostate cancer. Mol Cancer Ther 4(4):505–515

    Article  CAS  PubMed  Google Scholar 

  24. Vinh LB, Nguyet NTM, Yang SY, Kim JH, Thanh NV, Cuong NX, Nam NH, Minh CV, Hwang I, Kim YH (2019) Cytotoxic triterpene saponins from the mangrove Aegiceras corniculatum. Nat Prod Res 33(5):628–634

    Article  CAS  PubMed  Google Scholar 

  25. Garcia-Sosa K, Sanchez-Medina A, Alvarez SL, Zacchino S, Veitch NC, Sima-Polanco P, Pena-Rodriguez LM (2011) Antifungal activity of sakurasosaponin from the root extract of Jacquinia flammea. Nat Prod Res 25(12):1185–1189

    Article  CAS  PubMed  Google Scholar 

  26. Sanchez-Medina A, Pena-Rodriguez LM, May-Pat F, Karagianis G, Waterman PG, Mallet AI, Habtemariam S (2010) Identification of sakurasosaponin as a cytotoxic principle from Jacquinia flammea. Nat Prod Commun 5(3):365–368

    CAS  PubMed  Google Scholar 

  27. Merseburger AS, Hupe MC (2016) An update on triptorelin: current thinking on androgen deprivation therapy for prostate cancer. Adv Ther 33(7):1072–1093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Banerjee PP, Banerjee S, Brown TR, Zirkin BR (2018) Androgen action in prostate function and disease. Am J Clin Exp Urol 6(2):62–77

    PubMed  PubMed Central  Google Scholar 

  29. Newman DJ, Cragg GM (2016) Natural products as sources of new drugs from 1981 to 2014. J Nat Prod 79(3):629–661

    Article  CAS  PubMed  Google Scholar 

  30. Cragg GM (1830) Newman DJ (2013) Natural products: a continuing source of novel drug leads. Biochim Biophys Acta 6:3670–3695

    Google Scholar 

  31. Kim R (2005) Unknotting the roles of Bcl-2 and Bcl-xL in cell death. Biochem Biophys Res Commun 333(2):336–343

    Article  CAS  PubMed  Google Scholar 

  32. Antignani A, Youle RJ (2006) How do Bax and Bak lead to permeabilization of the outer mitochondrial membrane? Curr Opin Cell Biol 18(6):685–689

    Article  CAS  PubMed  Google Scholar 

  33. Kim R, Emi M, Tanabe K (2005) Caspase-dependent and -independent cell death pathways after DNA damage (Review). Oncol Rep 14(3):595–599

    CAS  PubMed  Google Scholar 

  34. Kim R, Emi M, Tanabe K (2006) Role of mitochondria as the gardens of cell death. Cancer Chemother Pharmacol 57(5):545–553

    Article  CAS  PubMed  Google Scholar 

  35. Kuwana T, Newmeyer DD (2003) Bcl-2-family proteins and the role of mitochondria in apoptosis. Curr Opin Cell Biol 15(6):691–699

    Article  CAS  PubMed  Google Scholar 

  36. Kim E, Jung Y, Choi H, Yang J, Suh JS, Huh YM, Kim K, Haam S (2010) Prostate cancer cell death produced by the co-delivery of Bcl-xL shRNA and doxorubicin using an aptamer-conjugated polyplex. Biomaterials 31(16):4592–4599

    Article  CAS  PubMed  Google Scholar 

  37. Yamanaka K, Rocchi P, Miyake H, Fazli L, So A, Zangemeister-Wittke U, Gleave ME (2006) Induction of apoptosis and enhancement of chemosensitivity in human prostate cancer LNCaP cells using bispecific antisense oligonucleotide targeting Bcl-2 and Bcl-xL genes. BJU Int 97(6):1300–1308

    Article  CAS  PubMed  Google Scholar 

  38. Meng Y, Tang W, Dai Y, Wu X, Liu M, Ji Q, Ji M, Pienta K, Lawrence T, Xu L (2008) Natural BH3 mimetic (-)-gossypol chemosensitizes human prostate cancer via Bcl-xL inhibition accompanied by increase of Puma and Noxa. Mol Cancer Ther 7(7):2192–2202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Pilling AB, Hwang C (2019) Targeting prosurvival BCL2 signaling through Akt blockade sensitizes castration-resistant prostate cancer cells to enzalutamide. Prostate 79(11):1347–1359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the “Procurement and development of foreign biological resources” funded by the Ministry of Science ICT and Future Planning of the Korean government (NRF-2016K1A1A8A01938718) and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2018R1D1A1B07047406 and NRF-2018R1D1A1B07044392).

Author information

Author notes

  1. In-Sung Song and Yu Jeong Jeong contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 138-736, Republic of Korea

    In-Sung Song, Yu Jeong Jeong, Jueun Kim & Sung-Wuk Jang

  2. Asan Medical Center, Asan Medical Institute of Convergence Science and Technology, University of Ulsan College of Medicine, Seoul, 138-736, Republic of Korea

    Yu Jeong Jeong, Jueun Kim & Sung-Wuk Jang

  3. Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, 138-736, Republic of Korea

    Sung-Wuk Jang

  4. Graduate School of Biotechnology, Kyung Hee University, Yongin, Gyeonggi, 446-701, Republic of Korea

    Kyoung-Hwa Seo & Nam-In Baek

  5. Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 138-736, Republic of Korea

    Yunlim Kim & Choung-Soo Kim

Authors
  1. In-Sung Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu Jeong Jeong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jueun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kyoung-Hwa Seo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nam-In Baek
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yunlim Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Choung-Soo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sung-Wuk Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

I-SS and S-WJ designed the research; K-HS and N-IB isolated and identified S-saponin; I-SS, YJJ, JEK, and JS performed the research; I-SS, YJJ, JEK, JS, and S-WJ analyzed the data; and I-SS and S-WJ wrote the paper.

Corresponding authors

Correspondence to Choung-Soo Kim or Sung-Wuk Jang.

Ethics declarations

Conflict of interest

No potential conflicts of interest are disclosed.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 281 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Song, IS., Jeong, Y.J., Kim, J. et al. Pharmacological inhibition of androgen receptor expression induces cell death in prostate cancer cells. Cell. Mol. Life Sci. 77, 4663–4673 (2020). https://doi.org/10.1007/s00018-019-03429-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-019-03429-2

Keywords

Search

Navigation