Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Regulation of androgen receptor transcriptional activity by rapamycin in prostate cancer cell proliferation and survival

Oncogene volume 27, pages 7106–7117 (2008)Cite this article

Abstract

The mTOR (mammalian target of rapamycin) inhibitor rapamycin caused growth arrest in both androgen-dependent and androgen-independent prostate cancer cells; however, long-term treatment induced resistance to the drug. The aim of this study was to investigate methods that can overcome this resistance. Here, we show that rapamycin treatment stimulated androgen receptor (AR) transcriptional activity, whereas suppression of AR activity with the antiandrogen bicalutamide sensitized androgen-dependent, as well as AR-sensitive androgen-independent prostate cancer cells, to growth inhibition by rapamycin. Further, the combination of rapamycin and bicalutamide, but not the individual drugs, induced significant levels of apoptosis in prostate cancer cells. The net effect of rapamycin is determined by its individual effects on the mTOR complexes mTORC1 (mTOR/raptor/GβL) and mTORC2 (mTOR/rictor/sin1/GβL). Inhibition of both mTORC1 and mTORC2 by rapamycin-induced apoptosis, whereas rapamycin-stimulation of AR transcriptional activity resulted from the inhibition of mTORC1, but not mTORC2. The effect of rapamycin on AR transcriptional activity was mediated by the phosphorylation of the serine/threonine kinase Akt, which also partially mediated apoptosis induced by rapamycin and bicalutamide. These results indicate the presence of two parallel cell-survival pathways in prostate cancer cells: a strong Akt-independent, but rapamycin-sensitive pathway downstream of mTORC1, and an AR-dependent pathway downstream of mTORC2 and Akt, that is stimulated by mTORC1 inhibition. Thus, the combination of rapamycin and bicalutamide induce apoptosis in prostate cancer cells by simultaneously inhibiting both pathways and hence would be of therapeutic value in prostate cancer treatment.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  • Agus DB, Cordon-Cardo C, Fox W, Drobnjak M, Koff A, Golde DW et al. (1999). Prostate cancer cell cycle regulators: response to androgen withdrawal and development of androgen independence. J Natl Cancer Inst 91: 1869–1876.

    Article  CAS  Google Scholar 

  • Boehmer A, Anastasiadis AG, Feyerabend S, Nagele U, Kuczyk M, Schilling D et al. (2005). Docetaxel, estramustine and prednisone for hormone-refractory prostate cancer: a single-center experience. Anticancer Res 25: 4481–4486.

    CAS  PubMed  Google Scholar 

  • Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS et al. (1994). A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369: 756–758.

    Article  CAS  Google Scholar 

  • Cao C, Subhawong T, Albert JM, Kim KW, Geng L, Sekhar KR et al. (2006). Inhibition of mammalian target of rapamycin or apoptotic pathway induces autophagy and radiosensitizes PTEN null prostate cancer cells. Cancer Res 66: 10040–10047.

    Article  CAS  Google Scholar 

  • Cinar B, De Benedetti A, Freeman MR . (2005). Post-transcriptional regulation of the androgen receptor by Mammalian target of rapamycin. Cancer Res 65: 2547–2553.

    Article  CAS  Google Scholar 

  • Edwards J, Bartlett JM . (2005). The androgen receptor and signal-transduction pathways in hormone-refractory prostate cancer. Part 1: modifications to the androgen receptor. BJU Int 95: 1320–1326.

    Article  CAS  Google Scholar 

  • Gao N, Zhang Z, Jiang BH, Shi X . (2003). Role of PI3K/AKT/mTOR signaling in the cell cycle progression of human prostate cancer. Biochem Biophys Res Commun 310: 1124–1132.

    Article  CAS  Google Scholar 

  • Ghosh PM, Bedolla R, Mikhailova M, Kreisberg JI . (2002). RhoA-dependent murine prostate cancer cell proliferation and apoptosis: role of protein kinase Czeta. Cancer Res 62: 2630–2636.

    CAS  PubMed  Google Scholar 

  • Ghosh PM, Ghosh-Choudhury N, Moyer ML, Mott GE, Thomas CA, Foster BA et al. (1999). Role of RhoA activation in the growth and morphology of a murine prostate tumor cell line. Oncogene 18: 4120–4130.

    Article  CAS  Google Scholar 

  • Ghosh PM, Malik SN, Bedolla RG, Wang Y, Mikhailova M, Prihoda TJ et al. (2005). Signal transduction pathways in androgen-dependent and -independent prostate cancer cell proliferation. Endocr Relat Cancer 12: 119–134.

    Article  CAS  Google Scholar 

  • Ghosh PM, Mikhailova M, Bedolla R, Kreisberg JI . (2001). Arginine vasopressin stimulates mesangial cell proliferation by activating the epidermal growth factor receptor. Am J Physiol Renal Physiol 280: F972–F979.

    Article  CAS  Google Scholar 

  • Gingras AC, Raught B, Sonenberg N . (2001). Regulation of translation initiation by FRAP/mTOR. Genes Dev 15: 807–826.

    Article  CAS  Google Scholar 

  • Hartig PC, Bobseine KL, Britt BH, Cardon MC, Lambright CR, Wilson VS et al. (2002). Development of two androgen receptor assays using adenoviral transduction of MMTV-luc reporter and/or hAR for endocrine screening. Toxicol Sci 66: 82–90.

    Article  CAS  Google Scholar 

  • Hresko RC, Mueckler M . (2005). mTOR.RICTOR is the Ser473 kinase for Akt/protein kinase B in 3T3-L1 adipocytes. J Biol Chem 280: 40406–40416.

    Article  CAS  Google Scholar 

  • Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A et al. (2004). Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6: 1122–1128.

    Article  CAS  Google Scholar 

  • Kremer CL, Klein RR, Mendelson J, Browne W, Samadzedeh LK, Vanpatten K et al. (2006). Expression of mTOR signaling pathway markers in prostate cancer progression. Prostate 66: 1203–1212.

    Article  CAS  Google Scholar 

  • Lee CH, Inoki K, Guan KL . (2007). mTOR pathway as a target in tissue hypertrophy. Annu Rev Pharmacol Toxicol 47: 443–467.

    Article  CAS  Google Scholar 

  • Lin HK, Hu YC, Yang L, Altuwaijri S, Chen YT, Kang HY et al. (2003). Suppression versus induction of androgen receptor functions by the phosphatidylinositol 3-kinase/Akt pathway in prostate cancer LNCaP cells with different passage numbers. J Biol Chem 278: 50902–50907.

    Article  CAS  Google Scholar 

  • Lu S, Liu M, Epner DE, Tsai SY, Tsai MJ . (1999). Androgen regulation of the cyclin-dependent kinase inhibitor p21 gene through an androgen response element in the proximal promoter. Mol Endocrinol 13: 376–384.

    Article  CAS  Google Scholar 

  • Persad S, Attwell S, Gray V, Mawji N, Deng JT, Leung D et al. (2001). Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase: critical roles for kinase activity and amino acids arginine 211 and serine 343. J Biol Chem 276: 27462–27469.

    Article  CAS  Google Scholar 

  • Petrylak D . (2005). Therapeutic options in androgen-independent prostate cancer: building on docetaxel. BJU Int 96 (Suppl 2): 41–46.

    Article  CAS  Google Scholar 

  • Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH . (1994). RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78: 35–43.

    Article  CAS  Google Scholar 

  • Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H et al. (2004). Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14: 1296–1302.

    Article  CAS  Google Scholar 

  • Sarbassov DD, Ali SM, Sabatini DM . (2005a). Growing roles for the mTOR pathway. Curr Opin Cell Biol 17: 596–603.

    Article  CAS  Google Scholar 

  • Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF et al (2006). Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22: 159–168.

    Article  CAS  Google Scholar 

  • Sarbassov DD, Guertin DA, Ali SM, Sabatini DM . (2005b). Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307: 1098–1101.

    Article  CAS  Google Scholar 

  • Sharef S, Jac J, Khan M, Amato R . (2006). Rapamycin for androgen-independent prostrate cancer (AIPC). Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), pp 14584.

  • Shi Y, Yan H, Frost P, Gera J, Lichtenstein A . (2005). Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade. Mol Cancer Ther 4: 1533–1540.

    Article  CAS  Google Scholar 

  • Tzatsos A, Kandror KV . (2006). Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation. Mol Cell Biol 26: 63–76.

    Article  CAS  Google Scholar 

  • Wu L, Birle DC, Tannock IF . (2005). Effects of the mammalian target of rapamycin inhibitor CCI-779 used alone or with chemotherapy on human prostate cancer cells and xenografts. Cancer Res 65: 2825–2831.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr Hsing-Jien Kung for critical reading of the manuscript, Dr Barry Furr, AstraZeneca, Cheshire, UK, for the gift of bicalutamide (Casodex), Dr Bandana Chatterjee, University of Texas Health Science Center at San Antonio (UTHSCSA) for hPSA-luc construct; Dr LuZhe Sun, UTHSCSA, for β-gal construct and LNAI cell line. We are grateful to Sherra Johnson and Naveen K Krishnegowda for technical assistance in some of the experiments described. This study was supported by a Merit award from the Department of Veterans Affairs and award CA109057 from the National Cancer Institute.

Author information

Authors and Affiliations

  1. School of Medicine, University of California Davis, Sacramento, CA, USA

    Y Wang, S Bose, C-X Pan, R W deVere White & P M Ghosh

  2. VA Northern California Health Care System, Mather, CA, USA

    Y Wang, C-X Pan & P M Ghosh

  3. University of Texas Health Science Center, San Antonio, TX, USA

    M Mikhailova

Authors
  1. Y Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Mikhailova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Bose
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C-X Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R W deVere White
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P M Ghosh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P M Ghosh.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, Y., Mikhailova, M., Bose, S. et al. Regulation of androgen receptor transcriptional activity by rapamycin in prostate cancer cell proliferation and survival. Oncogene 27, 7106–7117 (2008). https://doi.org/10.1038/onc.2008.318

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2008.318

Keywords

This article is cited by

Search

Advanced search

Quick links