Time-dependent resveratrol-mediated mRNA and protein expression associated with cell cycle in WR-21 cells containing mutated human c-Ha-Ras.
Cancer results from an undesirable imbalance between cellular proliferation and apoptosis. Both processes may be modulated at the level of gene expression, viz., p53 and c-Ha-ras, by dietary bioactive components such as resveratrol. We tested the time-dependent effect of resveratrol on gene and protein expression in WR-21 cells containing a mutated human c-Ha-ras oncogene. We demonstrate cyclic resveratrol-mediated expression of p53, mdm2, p21(cip/waf), Rb, and cyclin G at both the RNA and the protein level at <8 h. However, ras was not differentially expressed at either the RNA or the protein level. p53 was upregulated followed by p21cip/waf, then mdm2, and cyclin G, all downstream p53-activated targets. RNA transcription increased at >8 h for all genes except p53, but protein levels did not suggest uncoupling of transcription and translation. At 24 h, both p53 and Rb expression returned to baseline, suggesting collapse of DNA structure and spindle assembly checkpoints characteristic of mitotic catastrophe. In summary, resveratrol at <8 h induced p53-mediated effects, including apoptosis and cell-cycle arrest (G2/M). However, later, it induced cell-cycle checkpoint dysfunction, indicative of mitotic catastrophe. Thus, future studies should better elucidate the temporal mechanism of the dietary bioactive agent resveratrol on cancer cells.
Young
Leeanne F
LF
Nutrition and Cancer Laboratory, Department of Nutritional Sciences, Pennsylvania State University, University Park, USA.
Martin
Keith R
KR
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000032:analysis* / Q000235:genetics*; D045744:Cell Line, Tumor; D056746:Cyclin G; D056766:Cyclin G1; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis / Q000235:genetics; D016213:Cyclins / Q000032:analysis / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D016158:Genes, p53 / Q000235:genetics; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D051379:Mice; D009154:Mutation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis*; D000077185:Resveratrol; D016160:Retinoblastoma Protein / Q000032:analysis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012468:Salivary Gland Neoplasms; D013267:Stilbenes / Q000494:pharmacology*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D016588:Anticarcinogenic Agents; C534702:CCNG1 protein, human; C534703:Ccng1 protein, mouse; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D056746:Cyclin G; D056766:Cyclin G1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D000077185:Resveratrol