Fatty acids synthesis occurs at very high rates in tumor tissues, as first demonstrated more than half a century ago. Importantly, 14C glucose incorporation studies have shown that in tumor cells almost all fatty acids derive from de novo synthesis despite adequate nutritional supply. Prostate adenocarcinomas (PCa) overexpressing FAS display aggressive biologic behavior, suggesting that FAS overexpression confers a selective growth advantage. We have demonstrated that deregulated FAS expression in immortalized human prostate epithelial cells and as a transgene directed to the murine prostate results in invasive adenocarcinoma and prostatic intraepithelial neoplasia, respectively. The metabolic syndrome (MS), characterized by insulin resistance, central obesity and hypertension, is associated with inactivation of the master energy-sensor kinase AMPK and has recently been related to higher PCa incidence in large epidemiological studies. AMPK, when activated, inhibits FAS activity abolishing its oncogenic properties. Our preliminary data demonstrate that low serum levels of adiponectin, an endogenous activator of AMPK, significantly predict poor PCa survival. Taken together, these results strongly suggest a biological link between the metabolic syndrome, AMPK, FAS and PCa. The overarching hypothesis of this proposal is that FAS overexpression is the effector tumorigenic pathway of sustained AMPK inhibition. To validate this hypothesis, we will utilize a multidisciplinary approach that combines cell biology, animal model studies, tissue-based approaches and germline polymorphism correlations with PCa progression in large, annotated cohorts of PCa patients. Specifically, we will a) determine whether AMP kinase is a molecular target for inhibiting FAS activity;b) assess selected potential mechanisms of FAS mediated oncogenicity in PCa such as activation of pathways by palmitoylation of key regulatory genes c) assess whether genetic variations in the loci encoding AMPK, FAS, and their regulatory genes are predictors of prostate cancer progression and survival using haplotype tagging single nucleotide polymorphisms (SNPs);and d) relate the functional status of the FAS/AMPK axis to the metabolic syndrome in tissues from the same cohorts. The experiments proposed will establish FAS as a metabolic oncogene in prostate cancer, will solidify the link between the metabolic syndrome, obesity and prostate cancer through the master energy regulator kinase AMPK and establish FAS, and its regulators/effectors, as therapeutic targets in PCa.

Public Health Relevance

In this proposal we are studying the role of key metabolic enzymes in prostate cancer. We are specifically focusing on a metabolic enzyme which is central to the control of obesity and blood glucose control in humans. The data resulting from this proposal, which includes epidemiologic, mouse model and human tumor analyses, will provide the long sought molecular link between diet, obesity and prostate cancer. In addition, this research that will likely results in novel therapeutic approaches in this disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA131945-05
Application #
8301013
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Mohla, Suresh
Project Start
2008-09-26
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$339,794
Indirect Cost
$93,232
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Kenfield, Stacey A; Batista, Julie L; Jahn, Jaquelyn L et al. (2016) Development and Application of a Lifestyle Score for Prevention of Lethal Prostate Cancer. J Natl Cancer Inst 108:
Yang, Meng; Ayuningtyas, Azalea; Kenfield, Stacey A et al. (2016) Blood fatty acid patterns are associated with prostate cancer risk in a prospective nested case-control study. Cancer Causes Control 27:1153-61
Yang, Meng; Sesso, Howard D; Colditz, Graham A et al. (2016) Effect Modification by Time Since Blood Draw on the Association Between Circulating Fatty Acids and Prostate Cancer Risk. J Natl Cancer Inst 108:
Sinnott, Jennifer A; Peisch, Sam; Tyekucheva, Svitlana et al. (2016) Prognostic Utility of a New mRNA Expression Signature of Gleason Score. Clin Cancer Res :
Cacciatore, Stefano; Loda, Massimo (2015) Innovation in metabolomics to improve personalized healthcare. Ann N Y Acad Sci 1346:57-62
Tyekucheva, Svitlana; Martin, Neil E; Stack, Edward C et al. (2015) Comparing Platforms for Messenger RNA Expression Profiling of Archival Formalin-Fixed, Paraffin-Embedded Tissues. J Mol Diagn 17:374-81
Zadra, Giorgia; Batista, Julie L; Loda, Massimo (2015) Dissecting the Dual Role of AMPK in Cancer: From Experimental to Human Studies. Mol Cancer Res 13:1059-72
Hoffmann, Thomas J; Van Den Eeden, Stephen K; Sakoda, Lori C et al. (2015) A large multiethnic genome-wide association study of prostate cancer identifies novel risk variants and substantial ethnic differences. Cancer Discov 5:878-91
Martin, Neil E; Gerke, Travis; Sinnott, Jennifer A et al. (2015) Measuring PI3K Activation: Clinicopathologic, Immunohistochemical, and RNA Expression Analysis in Prostate Cancer. Mol Cancer Res 13:1431-40
Yang, Meng; Kenfield, Stacey A; Van Blarigan, Erin L et al. (2015) Dairy intake after prostate cancer diagnosis in relation to disease-specific and total mortality. Int J Cancer 137:2462-9

Showing the most recent 10 out of 48 publications