Dietary Saturated Fatty Acids Promote Src Kinase-Mediated Prostate Tumor Progression
Abstract
Rationale: Studies on the pattern of prostate cancer patient population show that patients on a high-fat diet or certain saturated fatty acids are associated with advanced stages of prostate cancer and increased risk of mortality in prostate cancer. This correlation raises the question of how dietary saturated fatty acids promote prostate cancer progression in advanced prostate cancer. Additionally, it is important to determine which oncogene could mediate prostate tumor progression under a high-fat diet. Src family kinases (SFKs) are a group of normal genes that can become oncogenes if they are overexpressed. Many studies have reported that the expression and activity of SFKs are frequently elevated in advanced prostate cancer. The importance of SFKs is further emphasized in that inhibiting SFKs shows clinic benefits in advanced prostate cancer. The functionality of SFKs requires attachment of myristate, a 14 carbon saturated fatty acid to the protein, a process called protein myristoylation. It has been reported that myristoylation of SFKs is important for the protein to be at the right location to function. Our preliminary study shows that a high-fat diet significantly promotes the growth of Src kinase-induced prostate tumors. Additionally, the inability to myristoylate Src kinase prevents prostate tumorigenesis under a high-fat diet. This suggests that Src kinase is an important factor in promoting tumor progression under a high-fat diet and myristoylation is essential for induction on its activity. Based on our preliminary results, we intend to block myristoylation of Src kinase to inhibit high-fat diet-induced tumor progression. The attachment of myristate to SFKs is catalyzed by an enzyme, called N-myristoyltransferase (NMT). This catalytic process requires the conversion of myristate to myristoyl-CoA. In collaboration with a research group at the Medical University of South Carolina, we have examined a panel of compounds, which are analogs of myristoyl-CoA. We have identified that compounds such as LCL1/4 reduce the activity of Src kinase and blocks its location at the cytoplasmic membrane. Scientific Objective: The objective of this proposal is to determine if increased expression of SFKs is the basis for the correlation of consumption of high-fat diet with prostate tumor progression and to understand why a high-fat diet promotes the activity of Src kinase. This knowledge will help us to better understand dietary choice as a strategy in optimizing the physical health of prostate cancer patients. Additionally, this study will investigate if analogs of myristoyl-CoA inhibit myristoylation of Src kinase and its mediated tumor progression. Ultimate Applicability and Contribution of the Research: The SFKs are highly elevated in advanced-stage prostate cancer patients, in particular in patients with metastatic prostate cancers. This study will help these patients to understand that dietary choice is important for tumor progression and will provide suggestions on a good choice of diet. Additionally, the identified compounds that inhibit the myristoylation of Src kinase will inhibit its activity and suppress Src-mediated tumor progression. The obtained knowledge could be immediately applied clinically to dictate the daily consumption in the patient s diet with no risk, but benefit in attenuation of tumor progression. Furthermore, this study will promote the chemical inhibitor to preclinical trials as a potential treatment option for advanced stages of prostate cancer. This study also attempts to investigate the fundamental biological process of how protein modification is related to its localization in the plasma membrane and its biological function under the influence of diet. Studying the myristoylation process of SFKs will help us understand the role of post-translational modification in the molecular signal transduction during prostate cancer initiation and progression.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510507
Entities
People
- Houjian Cai
Organizations
- United States Army
- University of Georgia