Resveratrol induces prostate cancer cell entry into s phase and inhibits DNA synthesis.
Resveratrol has an apoptotic effect on a variety of cancer cells. Changes in cell cycle regulatory processes contributing to the antiproliferative effect of resveratrol remain largely unknown. Our studies revealed that, in androgen-sensitive LNCaP cells, the effect of resveratrol on DNA synthesis varied dramatically depending on the concentration and the duration of treatment. In 1-h-treated cells, resveratrol showed only an inhibitory effect on DNA synthesis, which increased with increasing concentration (IC50 = 20 microM). However, when treatment duration was extended to 24 h, we observed a dual effect of resveratrol on DNA synthesis. At 5 to 10 microM it caused a 2- to 3-fold increase in DNA synthesis, and at > or =15 microM, it inhibited DNA synthesis. The increase in DNA synthesis was seen only in LNCaP cells, but not in androgen-independent DU145 prostate cancer cells or in NIH3T3 fibroblast cells. The resveratrol-induced increase in DNA synthesis was associated with enrichment of LNCaP cells in S phase, and a concurrent decrease in nuclear p21Cipl and p27Kip1 levels. Furthermore, consistent with the entry of LNCaP cells into S phase, there was a dramatic increase in nuclear Cdk2 activity associated with both cyclin A and cyclin E. Taken together, our observations indicate that LNCaP cells, treated with resveratrol, are induced to enter into S phase, but subsequent progression through S phase is limited by the inhibitory effect of resveratrol on DNA synthesis, particularly at concentrations above 15 microM. Therefore, this unique ability of resveratrol to exert opposing effects on two important processes in cell cycle progression, induction of S phase and inhibition of DNA synthesis, may be responsible for its apoptotic and antiproliferative effects.
Kuwajerwala
Nafisa
N
Vattikuti Urology Institute, Henry Ford Health Sciences Center, Detroit, Michigan 48202, USA.
Cifuentes
Eugenia
E
Gautam
Subhash
S
Menon
Mani
M
Barrack
Evelyn R
ER
Reddy
G Prem Veer
GP
D000728:Androgens / Q000502:physiology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D019925:Cyclin A / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004273:DNA, Neoplasm / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D008297:Male; D051379:Mice; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077185:Resveratrol; D016196:S Phase / Q000187:drug effects*; D013267:Stilbenes / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D000728:Androgens; D000972:Antineoplastic Agents, Phytogenic; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D019925:Cyclin A; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004273:DNA, Neoplasm; D013267:Stilbenes; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D000077185:Resveratrol