Time-dependent resveratrol-mediated mRNA and protein expression associated with cell cycle in WR-21 cells containing
Leeanne F Young1, Keith R Martin
1Nutrition and Cancer Laboratory, Department of Nutritional Sciences, Pennsylvania State University, University Park, USA.
Abstract:
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.
Insights
Resveratrol, a dietary compound, initially triggers cancer cell apoptosis and cell-cycle arrest by upregulating p53. However, prolonged exposure leads to cell-cycle dysfunction and mitotic catastrophe, indicating complex temporal effects.
Area of Science:
- Molecular Biology
- Cancer Research
- Nutritional Science
Background:
- Cancer arises from dysregulated cellular proliferation and apoptosis.
- Dietary bioactive compounds, like resveratrol, can modulate gene expression involved in these processes.
- The human c-Ha-ras oncogene plays a role in cancer development.
Purpose of the Study:
- To investigate the time-dependent effects of resveratrol on gene and protein expression in cancer cells with a mutated c-Ha-ras oncogene.
- To elucidate the molecular mechanisms underlying resveratrol's impact on cell cycle regulation and apoptosis.
- To understand the temporal sequence of resveratrol's effects on key cancer-related genes.
Main Methods:
- Utilized WR-21 cells harboring a mutated human c-Ha-ras oncogene.
- Analyzed time-dependent changes in RNA and protein expression of p53, mdm2, p21(cip/waf), Rb, and cyclin G following resveratrol treatment.
- Assessed differential expression of c-Ha-ras at both RNA and protein levels.
Main Results:
- Resveratrol induced cyclic expression of p53, mdm2, p21(cip/waf), Rb, and cyclin G at both RNA and protein levels within 8 hours.
- p53 upregulation was followed by downstream targets: p21(cip/waf), mdm2, and cyclin G.
- At 24 hours, p53 and Rb expression returned to baseline, suggesting cell-cycle checkpoint dysfunction and potential mitotic catastrophe. c-Ha-ras expression remained unchanged.
Conclusions:
- Resveratrol exerts time-dependent, p53-mediated effects on cancer cells, initially inducing apoptosis and G2/M cell-cycle arrest.
- Later effects of resveratrol include cell-cycle checkpoint dysfunction, indicative of mitotic catastrophe.
- Further research is needed to fully understand the temporal mechanisms of resveratrol in cancer treatment.
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