Sensitization of TRAIL-resistant LNCaP cells by resveratrol (3, 4', 5 tri-hydroxystilbene): molecular mechanisms and therapeutic potential.
BACKGROUND
We have previously shown that prostate cancer LNCaP cells are resistant to TRAIL, and downregulation of PI-3K/Akt pathway by molecular and pharmacological means sensitizes cells to undergo apoptosis by TRAIL and curcumin. The purpose of this study was to examine the molecular mechanisms by which resveratrol sensitized TRAIL-resistant LNCaP cells.


RESULTS
Resveratrol inhibited growth and induced apoptosis in androgen-dependent LNCaP cells, but had no effect on normal human prostate epithelial cells. Resveratrol upregulated the expression of Bax, Bak, PUMA, Noxa, Bim, TRAIL-R1/DR4 and TRAIL-R2/DR5, and downregulated the expression of Bcl-2, Bcl-XL, survivin and XIAP. Treatment of LNCaP cells with resveratrol resulted in generation of reactive oxygen species, translocation of Bax and p53 to mitochondria, subsequent drop in mitochondrial membrane potential, release of mitochondrial proteins (cytochrome c, AIF, Smac/DIABLO and Omi/HtrA2), activation of caspase-3 and caspase-9 and induction of apoptosis. The ability of resveratrol to sensitize TRAIL-resistant LNCaP cells was inhibited by dominant negative FADD, caspase-8 siRNA or N-acetyl cysteine. Smac siRNA inhibited resveratrol-induced apoptosis, whereas Smac N7 peptide induced apoptosis and enhanced the effectiveness of resveratrol.


CONCLUSIONS
Resveratrol either alone or in combination with TRAIL or Smac can be used for the prevention and/or treatment of human prostate cancer.
Shankar
Sharmila
S
Department of Biochemistry, University of Texas Health Science Center at Tyler, Tyler, Texas, USA 75703. rakeh.srivastava@uthct.edu.
Chen
Qinghe
Q
Siddiqui
Imtiaz
I
Sarva
Krishna
K
Srivastava
Rakesh K
RK
Annu Rev Med. 2006;57:49-63
16409136
Cancer Res. 2001 Oct 15;61(20):7456-63
11606380
Nature. 1997 Sep 18;389(6648):300-5
9305847
Pathophysiology. 2000 Sep;7(3):153-163
10996508
Science. 1997 Apr 4;276(5309):111-3
9082980
J Exp Med. 1999 Jul 19;190(2):253-65
10432288
Science. 1997 Aug 8;277(5327):818-21
9242611
Biochim Biophys Acta. 2002 Mar 14;1602(1):47-59
11960694
J Clin Oncol. 2005 Nov 10;23(32):8152-60
16278466
J Biol Chem. 2003 Aug 22;278(34):31469-72
12835328
Nat Med. 1997 Jun;3(6):614-20
9176486
EMBO J. 1999 Nov 1;18(21):6027-36
10545114
Int J Mol Med. 2005 Dec;16(6):1125-38
16273296
Cancer Res. 2003 Apr 1;63(7):1712-21
12670926
J Biol Chem. 2005 Jan 21;280(3):2266-74
15537572
Nat Med. 2005 Jul;11(7):725-30
16015365
Cell. 2005 Jan 14;120(1):7-10
15652475
Biochem Soc Symp. 1999;66:1-15
10989652
Cancer Res. 2003 Sep 1;63(17):5390-400
14500373
Oncogene. 2005 Jul 7;24(29):4609-23
15897906
Neoplasia. 2001 Nov-Dec;3(6):535-46
11774036
In Vivo. 2005 Jan-Feb;19(1):37-60
15796155
Mol Cell Biol. 2003 Dec;23(23):8576-85
14612402
Cell Mol Life Sci. 1999 Jan;55(1):9-11
10065147
Curr Biol. 1997 Dec 1;7(12):R750-3
9382834
J Immunol. 1998 Sep 15;161(6):2833-40
9743343
Science. 2004 Jul 30;305(5684):626-9
15286356
Nat Cell Biol. 2004 May;6(5):443-50
15077116
Oncogene. 2001 Sep 20;20(42):6073-83
11593415
Oncogene. 2000 Aug 10;19(34):3840-8
10951577
J Biol Chem. 2000 May 26;275(21):16202-12
10821866
Carcinogenesis. 2007 Jun;28(6):1277-86
17277231
Oncogene. 2001 Apr 19;20(17):2122-33
11360196
Biochemistry. 1991 May 7;30(18):4480-6
2021638
J Exp Med. 1997 Oct 6;186(7):1165-70
9314565
EMBO J. 1997 Sep 1;16(17):5386-97
9311998
J Clin Invest. 2005 Oct;115(10):2640-7
16200197
Genes Dev. 1999 Feb 1;13(3):239-52
9990849
Science. 1991 Jul 5;253(5015):49-53
1905840
Nat Rev Cancer. 2002 Aug;2(8):594-604
12154352
Science. 2004 Feb 13;303(5660):1010-4
14963330
Cancer Lett. 2006 Jan 8;231(1):113-22
16356836
Mol Cell. 2003 Mar;11(3):577-90
12667443
Science. 1997 Jan 10;275(5297):218-20
8985016
Cell. 2005 Jun 3;121(5):671-4
15935754
Cancer Res. 2006 Mar 15;66(6):3126-36
16540663
Mol Cell Biochem. 2007 Oct;304(1-2):273-85
17636462
Cancer Metastasis Rev. 2002;21(2):111-24
12465750
Int J Oncol. 2004 May;24(5):1133-40
15067334
J Clin Invest. 1999 Jul;104(2):155-62
10411544
J Urol. 1999 Jan;161(1):152-5
10037388
Curr Biol. 1997 Dec 1;7(12):1003-6
9382840
Prostate. 2004 Sep 15;61(1):35-49
15287092
Mol Cell Biol Res Commun. 2000 Aug;4(2):67-75
11170835
Cancer Biol Ther. 2003 Jul-Aug;2(4 Suppl 1):S105-14
14508087
Nat Med. 1999 Feb;5(2):157-63
9930862
Drug Resist Updat. 2004 Apr;7(2):139-56
15158769
Nat Rev Cancer. 2002 Sep;2(9):647-56
12209154
Genes Dev. 1996 Nov 15;10(22):2859-69
8918887
Int J Oncol. 2007 Apr;30(4):905-18
17332930
Nat Rev Cancer. 2004 Oct;4(10):793-805
15510160
Immunity. 1997 Dec;7(6):813-20
9430226
Mol Cell Biol. 1999 Aug;19(8):5659-74
10409755
Cancer Res. 2003 Mar 1;63(5):1059-66
12615723
Immunol Today. 1997 Jan;18(1):44-51
9018974
Cancer Res. 2002 Sep 1;62(17):4929-37
12208743
Int J Oncol. 2003 Jan;22(1):5-13
12469179
Prostate. 2005 Feb 1;62(2):165-86
15389801
Science. 1998 Aug 28;281(5381):1305-8
9721089