Cancer cells gain growth advantages in the microenvironment by shifting cellular metabolism to aerobic glycolysis, the so-called Warburg effect. There is a growing interest in targeting aerobic glycolysis for cancer therapy by exploiting the differential susceptibility of malignant versus normal cells to glycolytic inhibition, of which the proof-of-concept is provided by the in vivo efficacy of dietary caloric restriction and natural product-based energy restriction-mimetic agents (ERMAs) such as resveratrol and 2-deoxyglucose (2-DG) in suppressing carcinogenesis in experimental animal models. The clinical applications of resveratrol and 2-DG, however, are hampered by their weak potencies. Our studies have identified thiazolidinediones (TZDs) as a novel class of ERMAs in that they elicited hallmark cellular responses characteristic of energy restriction, including transient induction of silent information regulator (Sirt)1 expression, activation of the intracellular fuel sensor AMP-activated protein kinase (AMPK), and endoplasmic reticulum (ER) stress, the interplay among which culminated in autophagic and apoptotic cell death. These results provided a molecular basis to conduct lead optimization of TZDs, which netted OSU-CG12 (CG12) exhibiting an-order-of-magnitude higher potency than resveratrol in restricting tumor metabolism by blocking glucose uptake. Thus, this competing renewal proposal is aimed at testing the hypothesis that the unique ability of CG12 to target energy metabolism has translational potential in prostate cancer prevention.
Three Specific Aims are proposed.
Aim 1 is to conduct the mechanistic characterization of the mode of action of CG12 in mediating energy restriction. We will identify the mechanism underlying the suppressive effects of CG12 on glucose utilization, examine the role of p53 in CG12-induced apoptotic and autophagic cell death, and investigate the mechanism underlying CG12-mediated suppression of HIF-1a, which plays a critical role in regulating cell metabolism through the metabolic switch to glycolysis and the development of resistance to 2-DG.
Aim 2 is to continue the lead optimization of CG12 to develop potent ERMAs.
Aim 3 is to assess the in vivo efficacy of an optimized ERMA to block prostate tumorigenesis in the TRAMP and PTEN-deficient mouse models. Together, the proposed studies will effectively translate our novel finding that TZDs uniquely target tumor metabolism to preclinical development of a novel class of ERMAs with significant chemopreventive potential.

Public Health Relevance

In men, prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer death. Our overall research goal is to develop novel agents that target the specific molecular and cellular defects in prostate cancer cells that make the clinical management and development of preventive strategies for this disease so challenging. We expect that this project will ultimately yield new drugs that will block or delay the development and/or the progression of prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA112250-07
Application #
8206642
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Perloff, Marjorie
Project Start
2004-12-01
Project End
2015-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
7
Fiscal Year
2012
Total Cost
$285,581
Indirect Cost
$98,315
Name
Ohio State University
Department
Other Health Professions
Type
Schools of Pharmacy
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Chuang, Hsiao-Ching; Chou, Chih-Chien; Kulp, Samuel K et al. (2014) AMPK as a potential anticancer target - friend or foe? Curr Pharm Des 20:2607-18
Lai, I-Lu; Chou, Chih-Chien; Lai, Po-Ting et al. (2014) Targeting the Warburg effect with a novel glucose transporter inhibitor to overcome gemcitabine resistance in pancreatic cancer cells. Carcinogenesis 35:2203-13
Chou, Chih-Chien; Salunke, Santosh B; Kulp, Samuel K et al. (2014) Prospects on strategies for therapeutically targeting oncogenic regulatory factors by small-molecule agents. J Cell Biochem 115:611-24
Chou, Chih-Chien; Lee, Kuen-Haur; Lai, I-Lu et al. (2014) AMPK reverses the mesenchymal phenotype of cancer cells by targeting the Akt-MDM2-Foxo3a signaling axis. Cancer Res 74:4783-95
Chu, Po-Chen; Kulp, Samuel K; Chen, Ching-Shih (2013) Insulin-like growth factor-I receptor is suppressed through transcriptional repression and mRNA destabilization by a novel energy restriction-mimetic agent. Carcinogenesis 34:2694-705
Ma, Yihui; McCarty, Samantha K; Kapuriya, Naval P et al. (2013) Development of p21 activated kinase-targeted multikinase inhibitors that inhibit thyroid cancer cell migration. J Clin Endocrinol Metab 98:E1314-22
Berman-Booty, Lisa D; Chu, Po-Chen; Thomas-Ahner, Jennifer M et al. (2013) Suppression of prostate epithelial proliferation and intraprostatic progrowth signaling in transgenic mice by a new energy restriction-mimetic agent. Cancer Prev Res (Phila) 6:232-41
Lee, Su-Lin; Chou, Chih-Chien; Chuang, Hsiao-Ching et al. (2013) Functional Role of mTORC2 versus Integrin-Linked Kinase in Mediating Ser473-Akt Phosphorylation in PTEN-Negative Prostate and Breast Cancer Cell Lines. PLoS One 8:e67149
Huang, Po-Hsien; Chuang, Hsiao-Ching; Chou, Chih-Chien et al. (2013) Vitamin E facilitates the inactivation of the kinase Akt by the phosphatase PHLPP1. Sci Signal 6:ra19
Berman-Booty, Lisa D; Sargeant, Aaron M; Rosol, Thomas J et al. (2012) A review of the existing grading schemes and a proposal for a modified grading scheme for prostatic lesions in TRAMP mice. Toxicol Pathol 40:5-17

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