237: Gene Expression Profiling of Prostate Cancers from Obese Men Identified HMGCS2 as a Novel Biomarker of Aggressive Prostate Cancer and as a Potential Therapeutic Target

Abstract

INTRODUCTION AND OBJECTIVE: Obesity is associated with aggressive prostate cancer (CaP). We hypothesized that identification of gene expression differences between CaPs from obese and normal weight men would provide valuable insight into the biology of aggressive CaP.METHODS: Gene expression patterns were compared between from CaP tissue from 8 very obese (BMI :::_35 kg/m 2 ) and 8 normal weight men (BMI 20-25 kg/m 2 ), matched for grade, stage, PSA, year of surgery, race, and age. In vitro cell viability was assessed via MTT assay. The effect of diet on CaP xenograft tumor growth was assessed in SCID mice.RESULTS: Gene expression differences between CaPs from obese and normal weight men were far greater than expected by chance alone. The most differentially expressed gene was 3-hydroxymethyl glutaryl coA synthase (HMGCS2), the rate limiting enzyme in ketone body production. Using a separate set of 36 CaPs, we verified that HMGCS2 was significantly lower in CaP from obese men and found that HMGCS2 was lower in high-grade CaP regardless of BMI. This suggests that decreased ketone body production may provide a growth advantage for aggressive CaP and/or ketone bodies (the end product of HMGCS2 activity) may be toxic to CaP cells. Treatment of CaP cells in vitro with physiological doses of ketone bodies or transfection of cells with HMGCS2 eDNA inhibited cell viability 10-75% and 40-60%, respectively. To test whether a ketogenic diet, which induces ketosis and upregulates HMGCS2, could delay CaP growth, we randomized 28 mice each to a low-fat, high-fat, or ketogenic diet. After 3 weeks, all mice were injected with LAPC-4 CaP cells. Mice on the ketogenic diet, despite initially consuming equal calories, lost significant amounts of weight and needed extra calories to maintain body weight. There was a trend, which did not reach significance, for the ketogenic diet to be associated with smaller tumors relative to a high-fat diet (p=0.06) and a low-fat diet (p=0.18).CONCLUSIONS: CaPs in obese men are molecularly distinct from CaPs among normal weight men. HMGCS2 is a new CaP biomarker that is related to both obesity and high-grade CaP. Our in vitro observations further suggest that HMGCS2 may be a new therapeutic target. Mice consuming a ketogenic diet consumed more calories, lost weight, and had a trend toward smaller tumors. If longer follow-up continues to demonstrate delayed tumor growth, a ketogenic diet may present an exciting new approach to CaP management.