Resveratrol regulates cellular PKC alpha and delta to inhibit growth and induce apoptosis in gastric cancer cells.
Resveratrol, a dietary phytoalexin, has emerged as a promising chemopreventive agent due to its antiproliferative and pro-apoptotic action toward cancer cells and its ability to inhibit tumor growth in animals. Gastric adenocarcinoma cells respond to resveratrol treatment with suppression of DNA synthesis, activation of nitric oxide synthase, induction of apoptosis and inhibition of total PKC and PKC alpha activity. Here we demonstrate that treatment of gastric adenocarcinoma SNU-1 cells with resveratrol results in time and concentration dependent accumulation of tumor suppressors p21(cip1/WAF-1) and p53 and is preceded by loss of membrane-associated PKC delta protein and a concomitant increase in cytosolic PKC alpha. Arrest of the cell cycle at transition of S to G(2)/M phases correlates with the profile of (3)H-thymidine incorporation and accumulation of p21(cip1/WAF-1) and was temporally dependent on increase of p53. SNU-1 cells respond to resveratrol treatment with up-regulation of both Fas and Fas-L proteins, whereas in KATO-III cells, with deleted p53, only Fas-L is increased after resveratrol treatment. Although Fas and Fas-L proteins in SNU-1 cells and Fas-L in KATO-III cells were elevated within 24 h of cell treatment with low concentrations of resveratrol, significant apoptotic response at these concentrations was observed only after 48 h. Altogether, our findings indicate that resveratrol engages PKC alpha and delta signals in gastric adenocarcinoma SNU-1 cells prior to up-regulation of antiproliferative and pro-apoptotic signals. The specific cell death signals engaged by resveratrol appear to be cell type dependent and suggest that resveratrol has chemopreventive potential even after mutational changes have occurred.
Atten
Mary Jo
MJ
Department of Medicine Division of Gastroenterology, Cook County Hospital, Chicago, IL 60612, USA.
Godoy-Romero
Ernesto
E
Attar
Bashar M
BM
Milson
Thomas
T
Zopel
Matthew
M
Holian
Oksana
O
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D053222:Fas Ligand Protein; D006801:Humans; D008562:Membrane Glycoproteins / Q000187:drug effects*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D000077185:Resveratrol; D013267:Stilbenes / Q000627:therapeutic use; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control
D016588:Anticarcinogenic Agents; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D013267:Stilbenes; D019001:Nitric Oxide Synthase; D011493:Protein Kinase C; D000077185:Resveratrol
Biochim Biophys Acta. 2003 Jan 20;1637(1):59-69
12527408
Drugs Exp Clin Res. 1999;25(2-3):79-85
10370868
Semin Cancer Biol. 1998;8(5):345-57
10101800
Clin Cancer Res. 2001 May;7(5):1466-73
11350919
Rev Physiol Biochem Pharmacol. 2001;142:1-96
11190577
Biochemistry. 1999 Oct 5;38(40):13244-51
10529197
Oncogene. 2000 May 4;19(19):2331-7
10822384
Int J Oncol. 1998 Apr;12(4):865-9
9499448
Microbios. 2001;104(408):79-85
11297014
J Exp Med. 1996 Dec 1;184(6):2399-404
8976194
Int J Cancer. 2001 Dec 1;94(5):615-22
11745454
J Biol Chem. 1997 Jan 24;272(4):2452-8
8999958
J Biol Chem. 2000 Mar 17;275(11):7574-82
10713064
Cancer Lett. 2000 Feb 1;148(2):181-8
10695995
Int J Hematol. 2000 Jul;72(1):12-9
10979203
J Exp Med. 1998 Dec 7;188(11):2033-45
9841917
Gen Pharmacol. 1998 Nov;31(5):721-8
9809468
J Pharm Pharmacol. 2000 Oct;52(10):1287-95
11092574
Carcinogenesis. 2000 Aug;21(8):1619-22
10910967
FASEB J. 2001 Aug;15(10):1798-800
11481234
Cancer Res. 2002 May 1;62(9):2488-92
11980638
Br J Haematol. 2000 May;109(2):405-12
10848832
Cancer Res. 2000 Jul 1;60(13):3477-83
10910059
Leuk Res. 1998 Jul;22(7):597-604
9680109
Hepatology. 1998 May;27(5):1265-74
9581680
J Biol Chem. 2003 Oct 17;278(42):41482-90
12902349
Am J Physiol Gastrointest Liver Physiol. 2002 May;282(5):G809-16
11960777
Science. 1997 Jan 10;275(5297):218-20
8985016
Biochem Biophys Res Commun. 1998 Sep 8;250(1):53-8
9735330
J Nutr. 2001 Aug;131(8):2197-203
11481417
Biochem J. 1999 Dec 15;344 Pt 3:921-8
10585882
Am J Gastroenterol. 2000 Jul;95(7):1849
10926010
J Med Chem. 1993 Oct 1;36(20):2950-5
8411012
J Cell Physiol. 1999 Jun;179(3):297-304
10228948
Biochem Pharmacol. 2001 Nov 15;62(10):1423-32
11709203
Circ Res. 1994 Feb;74(2):299-309
8293569
Cancer Lett. 2001 Feb 10;163(1):43-9
11163107
Mol Pharmacol. 2002 Oct;62(4):772-7
12237323
J Biol Chem. 1951 Nov;193(1):265-75
14907713
Cancer Surv. 1996;27:213-48
8909803
Clin Cancer Res. 2002 Mar;8(3):893-903
11895924
Pathol Res Pract. 1998;194(5):309-17
9651943
Hunan Yi Ke Da Xue Xue Bao. 1998;23(5):441-3
10682555
FEBS Lett. 1996 Jun 17;388(2-3):195-9
8690086
Cancer Metastasis Rev. 1994 Dec;13(3-4):411-31
7712599
Bone Marrow Transplant. 2000 Mar;25(6):639-45
10734298
Cell Death Differ. 2000 Sep;7(9):834-42
11042678
Biochem Pharmacol. 2000 Nov 1;60(9):1355-9
11008129