Downregulation of cyclin D1 is associated with decreased levels of p38 MAP kinases, Akt/PKB and Pak1 during chemopreventive effects of resveratrol in liver cancer cells.
Resveratrol is a naturally occurring phytoalexin with antioxidant activity. The chemopreventive effects of resveratrol against various types of cancer are well known, though the underlying molecular mechanisms of its action are still not identified. Hepatocellular carcinoma (HCC) is a one of the most lethal malignancies and there is no effective treatment till date. It is known that cyclin D1 is overexpressed in liver cancers. Accordingly we have studied the chemopreventive effects of resveratrol on cyclin D1 expression and the signaling pathways that regulate cyclin D1 in HepG2 cells. Flow cytometry and PCNA western blot data showed that resveratrol inhibits proliferation of HepG2 cells. Also, resveratrol treatment downregulated cyclin D1 as well as p38 MAP kinase, Akt and Pak1 expression and activity in HepG2 cells, suggesting that growth inhibitory activity of resveratrol is associated with the downregulation of cell proliferation and survival pathways. Furthermore, resveratrol treated cells showed increase in ERK activity suggesting possible sensitization to apoptosis. Thus in the present study, we report a three-dimensional relationship between the growth inhibitory effects of resveratrol - decrease in the levels of cyclin D1 - and downregulation of cell proliferation and survival pathways in HepG2 cells leading to cellular degenerative changes. These observations suggest that resveratrol has good potential as effective chemopreventive agent against liver cancer and warrant further studies.
Chemical Carcinogenesis Group, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai-410208, India.
Palak
P
Parekh
Leena
L
Motiwale
Nishigandha
N
Naik
K V K
KV
Rao
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000096:biosynthesis*; D015536:Down-Regulation; D005434:Flow Cytometry; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D018613:Microscopy, Confocal; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000077185:Resveratrol; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology*; D054462:p21-Activated Kinases / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D016588:Anticarcinogenic Agents; C530104:CCND1 protein, human; D013267:Stilbenes; D019938:Cyclin D1; C515903:PAK1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D054462:p21-Activated Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000077185:Resveratrol