Regulation of androgen receptor transcriptional activity by rapamycin in prostate cancer cell proliferation and survival.
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.
Wang
Y
Y
School of Medicine, University of California Davis, Sacramento, CA, USA.
Mikhailova
M
M
Bose
S
S
Pan
C-X
CX
deVere White
R W
RW
Ghosh
P M
PM
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
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
Genes Dev. 2001 Apr 1;15(7):807-26
11297505
BJU Int. 2005 Dec;96 Suppl 2:41-6
16359438
J Biol Chem. 2005 Dec 9;280(49):40406-16
16221682
Cancer Res. 2005 Apr 1;65(7):2547-53
15805247
Nat Cell Biol. 2004 Nov;6(11):1122-8
15467718
Curr Opin Cell Biol. 2005 Dec;17(6):596-603
16226444
J Natl Cancer Inst. 1999 Nov 3;91(21):1869-76
10547394
Prostate. 2006 Aug 1;66(11):1203-12
16652388
Toxicol Sci. 2002 Mar;66(1):82-90
11861975
Endocr Relat Cancer. 2005 Mar;12(1):119-34
15788644
Mol Cancer Ther. 2005 Oct;4(10):1533-40
16227402
Anticancer Res. 2005 Nov-Dec;25(6C):4481-6
16334130
Science. 2005 Feb 18;307(5712):1098-101
15718470
Mol Endocrinol. 1999 Mar;13(3):376-84
10076995
Curr Biol. 2004 Jul 27;14(14):1296-302
15268862
Oncogene. 1999 Jul 15;18(28):4120-30
10435593
Mol Cell Biol. 2006 Jan;26(1):63-76
16354680
J Biol Chem. 2001 Jul 20;276(29):27462-9
11313365
Cancer Res. 2006 Oct 15;66(20):10040-7
17047067
Cancer Res. 2002 May 1;62(9):2630-6
11980660
J Biol Chem. 2003 Dec 19;278(51):50902-7
14555644
Cell. 1994 Jul 15;78(1):35-43
7518356
BJU Int. 2005 Jun;95(9):1320-6
15892825
Cancer Res. 2005 Apr 1;65(7):2825-31
15805283
Biochem Biophys Res Commun. 2003 Oct 31;310(4):1124-32
14559232
Mol Cell. 2006 Apr 21;22(2):159-68
16603397
Annu Rev Pharmacol Toxicol. 2007;47:443-67
16968213
Am J Physiol Renal Physiol. 2001 Jun;280(6):F972-9
11352836
Nature. 1994 Jun 30;369(6483):756-8
8008069