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NUCLEAR RECEPTORS, ROS & CANCER BIOLOGY

ANGELINE ZHU YAN, BSc. (Hon) NGS Postgraduate student Department of Physiology MD11, 10 Medical Drive, #B1-07 Email: g0801845@nus.edu.sg Major Supervisor: Prof. Shazib Pervaiz Co-supervisor: Dr. Alan Prem Kumar Tel: (65) 6516-4445 Fax: (65) 6773-5461

Statins are widely prescribed as lipid-lowering agents in the primary and secondary prevention of cardiovascular disease. Of late, their potential cancer chemo-preventive and therapeutic effects have been highlighted. To that end, there is evidence of an inhibitory effect of statins in vitro, in vivo animal models, and observational and epidemiological studies, on colorectal carcinogenesis. More interestingly, a recent case-control study reported a 47% relative reduction in the risk of colorectal cancer associated with statin use after adjustment for other known risk factors. Despite the tremendous promise of statins as cancer chemopreventives, it is still too early to recommend their use outside the context of clinical trials as further investigations into the precise mechanisms and overall benefits in preventing colorectal cancer are warranted. On the backdrop of this, here we propose to study the effects of statins on human colo-rectal cancer cells in an effort to better understand their mechanism of anti-cancer activity. Notably, our preliminary data indicate a positive association between high Ras activity and sensitivity to simvastatin in the human colo-rectal cell line, HCT116. Moreover, this activity appears to involve Raf/MEK/ERK signaling pathway leading to accumulation of dephosphorylated form of the Bcl-2 family protein, BIM. Stimulated by these data, here we propose to: (1) confirm the effect of simvastatin on HCT116 and other colon carcinoma cell lines, (2) investigate if Ras status plays a role in simvastatin-induced apoptosis in colon cancer. To further elucidate the intracellular pathways by which statins mediate their antitumor activity we will investigate if (3) the effect of simvastatin is mediated by Raf/MEK/ERK pathway through activation of BIM. Furthermore, as Bim expression is under the transcriptional control of p53, we will ask (4) if the inhibitory effect of simvastatin in HCT116 is p53-dependent. Lastly, as there is increasing evidence that chemotherapeutic drugs work via intracellular ROS generation, such as hydrogen peroxide (H2O2), we propose to (5) determine simvastatin-induced apoptosis is a function of H2O2-mediated activation of the Raf/MEK/ERK pathway. Through these sets of experiments we hope to unravel novel intracellular pathways triggered by statins as a means to understand their chemo-preventive activity and potential for use as chemotherapeutic agents against colo-rectal cancers.