The androgen receptor directly targets the cellular Fas/FasL-associated death domain protein-like inhibitory protein gene to promote the androgen-independent growth of prostate cancer cells.
Androgens provide survival signals to prostate epithelial cells, and androgen ablation induces apoptosis in the prostate gland. However, the molecular mechanisms of actions of the androgen-signaling pathway in these processes are not fully understood. Here, we report that androgens induced expression of the cellular Fas/FasL-associated death domain protein-like inhibitory protein (c-FLIP) gene, which is a potent inhibitor of Fas/FasL-mediated apoptosis. The androgen receptor was recruited to the promoter of the c-FLIP gene in the presence of androgens. We found that c-FLIP promoter contained multiple functional androgen response elements. In addition, we show that c-FLIP overexpression accelerated progression to androgen independence by inhibiting apoptosis in LNCaP prostate tumors implanted in nude mice. Our results suggest that the androgen receptor affects survival and apoptosis of prostate cells through regulation of the c-FLIP gene in response to androgens.
Gao
Shen
S
Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 173, Houston, TX 77030-4009, USA.
Lee
Peng
P
Wang
Hua
H
Gerald
William
W
Adler
Michael
M
Zhang
Liying
L
Wang
Yun-Fang
YF
Wang
Zhengxin
Z
D000728:Androgens / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053222:Fas Ligand Protein; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics*; D015533:Transcriptional Activation
D000728:Androgens; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; C506387:Cflar protein, mouse; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D011944:Receptors, Androgen
Cell. 1993 Dec 17;75(6):1187-98
7903220
Mol Endocrinol. 2002 Oct;16(10):2323-37
12351697
Am J Pathol. 2002 Oct;161(4):1467-74
12368219
Eur Urol. 2004 Jun;45(6):683-91
15149739
Cancer Res. 2000 Dec 15;60(24):6841-5
11156376
Hum Gene Ther. 2001 Mar 20;12(5):549-61
11268287
J Steroid Biochem Mol Biol. 1999 Apr-Jun;69(1-6):307-13
10419007
Cancer Biol Ther. 2002 Sep-Oct;1(5):520-7
12496481
Steroids. 2004 Feb;69(2):79-85
15013685
Mol Cell Biol. 2003 Feb;23(4):1278-91
12556488
Oncogene. 2000 Nov 2;19(46):5251-8
11077442
J Clin Oncol. 2002 Jul 1;20(13):3001-15
12089231
Nature. 1970 Aug 15;227(5259):680-5
5432063
Nature. 2002 May 30;417(6888):563-7
12037571
Cancer Res. 1990 Sep 1;50(17):5382-6
2386943
Prostate. 1996 Apr;28(4):251-65
8602401
Urology. 1999 Nov;54(5):839-45
10565744
EMBO J. 2002 Jul 15;21(14):3704-14
12110583
Cancer Res. 2002 Aug 1;62(15):4499-506
12154061
Biotechniques. 1996 Jan;20(1):102-4, 106, 108-10
8770413
Nucleic Acids Res. 1997 Aug 1;25(15):3143-50
9224617
Clin Cancer Res. 2002 Sep;8(9):2942-51
12231540
Am J Pathol. 1995 Jun;146(6):1368-75
7778676
J Virol. 2003 Feb;77(4):2651-62
12552004
Oncogene. 1998 Apr 16;16(15):1913-20
9591774
Cancer Res. 2000 Nov 1;60(21):6134-41
11085537
Eur Urol. 1993;24(4):438-49
8287885
J Biol Chem. 2003 Apr 25;278(17):14956-60
12591938
Cancer Res. 1997 Sep 15;57(18):4075-81
9307296
J Pathol. 1999 Jan;187(2):237-41
10365100
Prostate. 2002 Dec 1;53(4):300-9
12430141
Trends Genet. 2002 May;18(5):S1-5
12047956
Prostate. 2000 Jul 1;44(2):91-103 Jul 1;44(2)
10881018
Prostate. 2001 Jan 1;46(1):76-85
11170135
Cell Death Differ. 1998 Apr;5(4):271-88
10200473
Clin Cancer Res. 2003 Jan;9(1):370-6
12538490
Mol Med. 2002 Nov;8(11):725-32
12520089
Cancer Res. 2003 Jul 1;63(13):3575-84
12839944
World J Urol. 1996;14(5):329-37
8912473
Nat Med. 1999 Mar;5(3):280-5
10086382
Cancer Biol Ther. 2002 Jul-Aug;1(4):401-6
12432255
Cancer Res. 1992 Dec 15;52(24):6940-4
1458483
Biotechniques. 1990 Apr;8(4):398-403
1692716
J Exp Med. 1999 Oct 4;190(7):1033-8
10510093
Vitam Horm. 2004;67:189-206
15110178
J Biol Chem. 2001 Jan 26;276(4):2943-52
11056175
Mol Cell Biol. 2001 Jul;21(14):4614-25
11416139
Cancer Res. 1999 Oct 1;59(19):5030-6
10519419