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

Y. Wang, M. Mikhailova, S. Bose, Chong-Xian Pan, Ralph W deVere White, Paramita M Ghosh

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)7106-7117
Number of pages12
JournalOncogene
Volume27
Issue number56
DOIs
StatePublished - Nov 27 2008

Fingerprint

Androgen Receptors
Sirolimus
Prostatic Neoplasms
Cell Survival
Cell Proliferation
Androgens
Apoptosis
Raptors
Androgen Antagonists
Protein-Serine-Threonine Kinases
Growth
Drug Resistance

Keywords

  • Akt
  • Androgen independence
  • Apoptosis
  • mTOR
  • Raptor
  • Rictor

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Regulation of androgen receptor transcriptional activity by rapamycin in prostate cancer cell proliferation and survival. / Wang, Y.; Mikhailova, M.; Bose, S.; Pan, Chong-Xian; deVere White, Ralph W; Ghosh, Paramita M.

In: Oncogene, Vol. 27, No. 56, 27.11.2008, p. 7106-7117.

Research output: Contribution to journalArticle

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