Novel Regulation and Oncogenic Mechanisms of Fatty Acid Synthase (FASN) in Aggressive Prostate Cancer
Abstract
Prostate cancer localized within the gland is readily curable, with surgery or radiotherapy as the most common treatment method for localized disease. For prostate cancer that has metastasized, hormone ablation is currently the first-line treatment. The removal of androgens results in tumor regression; however, patients will frequently relapse with castration-resistant disease. As the disease progresses, it eventually metastasizes to distant organs, including lymph nodes, lungs, liver, and bone. Changes in energy-sensing pathways and cellular metabolism are associated with the ability of prostate tumor cells to escape growth regulation and reliance on the prostate microenvironment. Folic acid also known as folate (the form naturally occurring in the body) is an essential vitamin that is important for cell division and growth through DNA and RNA synthesis, and maintaining the integrity of the DNA. In addition, folate is needed for single carbon transfer reactions for methylation that helps silence or activate DNA, RNA, proteins, and lipids. The folate pathway is considered a major energy-sensing pathway as cell growth and DNA synthesis is regulated by availability of the vitamin. Folate during development and in normal cells promotes energy pathway stability; however, folate induces dysregulated growth in tumor cells. We have found that folate is also a major regulator of the lipid synthesizing enzyme, fatty acid synthase (FASN). In normal cells the FASN lipid synthesis pathway is not an active due to dietary fat intake. However, in prostate cancer, it is highly upregulated and normal pathway control is lost. We have found by serendipity that the folate and FASN pathways interact, and may indeed be a major mechanism of castrate-resistant disease progression, mediated by a protein that is highly turned on in almost all prostate cancer and metastatic disease, Prostate-Specific Membrane Antigen (PSMA). Our objective, therefore, is to combine the research efforts of experts in folate metabolism, PSMA, and FASN together to understand how folate modulates FASN in prostate cancer, and ultimately provide dietary recommendations for prostate cancer patients regarding folic acid intake, and develop new therapeutic targets for this disease. In this study, we have four research aims to identify how dietary folate regulates FASN via PSMA in prostate cancer, and if abnormal localization to the nucleus of FASN can predict tumor aggressiveness. Our first aim will be to identify the mechanism(s) by which folate regulates FASN expression and pathway activity. We hypothesize that the major energy sensing pathway of AMPK is the direct link that connects the expression and lipid synthesizing activity of FASN with control by dietary folate. In addition, FASN in normal cells is a protein in the cytoplasm of the cell. However, in cancer, a significant amount of FASN is translocated to the nucleus. Bioinformatic analyses have given us leads to the potential nuclear function of FASN, where it might alter DNA structure and therefore gene expression. Thus, for our Aim 2, we will determine the role of nuclear FASN and identify the target(s) of its potential nuclear activity. Aim 3 will use mouse models to test how dietary folate and PSMA modulate FASN and tumor progression, in both an androgen-dependent and a castrate-resistant mouse model, utilizing inhibitors of PSMA that have been found safe in humans, to determine if these can abolish the effect of dietary folate on FASN expression. Finally, Aim 4 will use a set of patient tissues acquired from the Department of Veterans Affairs (VA) that have the known outcome of either documented metastases or no evidence of disease 5 years post-prostatectomy, to determine if nuclear FASN in the primary tumor could identify patients at risk of future metastasis, who may need different clinical care. This study may help patients with aggressive prostate cancer by re-establishing the normal
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710244
Entities
People
- Denise O Keefe
Organizations
- United States Army
- University of Texas Health Science Center at San Antonio