Suppression of Prostate Epithelial Proliferation and Intraprostatic Progrowth Signaling in Transgenic Mice by a New Energy Restriction-Mimetic Agent

• Published in: Cancer prevention research (Philadelphia, Pa.) Pa.), 2013-03, Vol.6 (3), p.232-241
• Main Authors: BERMAN-BOOTY, Lisa D, CHU, Po-Chen, THOMAS-AHNER, Jennifer M, BOLON, Brad, DASHENG WANG, YANG, Tiffany, CLINTON, Steven K, KULP, Samuel K, CHEN, Ching-Shih
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Animals; Antineoplastic Agents - pharmacology; Biological and medical sciences; Blotting, Western; Cell Line, Tumor; Cell Proliferation - drug effects; Disease Models, Animal; Glycolysis - drug effects; Humans; Immunohistochemistry; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Miscellaneous; Oligonucleotide Array Sequence Analysis; Precancerous Conditions - metabolism; Precancerous Conditions - pathology; Prevention and actions; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Public health. Hygiene; Public health. Hygiene-occupational medicine; Signal Transduction - drug effects; Thiazolidinediones - pharmacology
• ISSN: 1940-6207; 1940-6215
• DOI: 10.1158/1940-6207.CAPR-12-0057

Cells undergoing malignant transformation often exhibit a shift in cellular metabolism from oxidative phosphorylation to glycolysis. This glycolytic shift, called the Warburg effect, provides a mechanistic basis for targeting glycolysis to suppress carcinogenesis through the use of dietary caloric restriction and energy restriction-mimetic agents (ERMA). We recently reported the development of a novel class of ERMAs that exhibits high potency in eliciting starvation-associated cellular responses and epigenetic changes in cancer cells though glucose uptake inhibition. The lead ERMA in this class, OSU-CG5, decreases the production of ATP and NADH in LNCaP prostate cancer cells. In this study, we examined the effect of OSU-CG5 on the severity of preneoplastic lesions in male transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. Daily oral treatment with OSU-CG5 at 100 mg/kg from 6 to 10 weeks of age resulted in a statistically significant decrease in the weight of urogenital tract and microdissected dorsal, lateral, and anterior prostatic lobes relative to vehicle controls. The suppressive effect of OSU-CG5 was evidenced by marked decreases in Ki67 immunostaining and proliferating cell nuclear antigen (PCNA) expression in the prostate. OSU-CG5 treatment was not associated with evidence of systemic toxicity. Microarray analysis indicated a central role for Akt, and Western blot analysis showed reduced phosphorylation and/or expression levels of Akt, Src, androgen receptor, and insulin-like growth factor-1 receptor in prostate lobes. These findings support further investigation of OSU-CG5 as a potential chemopreventive agent.