title: Regulation of androgen receptor transcriptional activity by rapamycin in prostate cancer cell proliferation and survival.
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/GbetaL) and mTORC2 (mTOR/rictor/sin1/GbetaL). 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.
authors.affiliation: School of Medicine, University of California Davis, Sacramento, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: M
authors.initials: M
authors.lastname: Mikhailova
authors.forename: S
authors.initials: S
authors.lastname: Bose
authors.forename: C-X
authors.initials: CX
authors.lastname: Pan
authors.forename: R W
authors.initials: RW
authors.lastname: deVere White
authors.forename: P M
authors.initials: PM
authors.lastname: Ghosh
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D011944:Receptors, Androgen / Q000378:metabolism*; D000076223:Regulatory-Associated Protein of mTOR; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C493245:CRTC2 protein, human; D002352:Carrier Proteins; D046912:Multiprotein Complexes; D011506:Proteins; C492571:RICTOR protein, human; C463659:RPTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D011944:Receptors, Androgen; D000076223:Regulatory-Associated Protein of mTOR; D014157:Transcription Factors; C494918:AKT1 protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
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