Fatty Acid Synthase Activity as a Target for c-Met Driven Prostate Cancer
Abstract
Prostate cancer (PCa) is the most common noncutaneous neoplasia diagnosed in men and represents roughly 10% of cancer-associated mortalities. The lethal phenotype of PCa is primarily characterized by progression of tumor cells to castration-resistance and metastasis. Organ-confined PCa is curable with surgery and/or radiation therapy, however, as the disease becomes metastatic, the likelihood of survival becomes minimal. Key influences in the progression to metastasis are growth factor receptors including the receptor tyrosine kinase c-Met. During this research period, I have acquired convincing data that the c-Met receptor tyrosine kinase is palmitoylated and that this palmitoylation regulates its stability. Inhibition of palmitoylation reduces the expression of c-Met in prostate cancer cell lines. This protein loss occurs post-transcriptionally and is associated with accumulation of c-Met in Golgi compartments. Using inhibitors to a number of internalization pathways, as well as surface biotinylation studies and confocal microscopy, we determined that inhibition of palmitoylation reduces the stability of newly synthesized c-Met as opposed to inducing internalization and degradation. Moreover, both an acyl-biotin exchange technique and a click-chemistry based palmitate-labeling protocol suggest c-Met itself is palmitoylated. Observing palmitoylation kinetics has provided evidence that c-Met is palmitoylated in the Golgi prior to cleavage of the c- Met precursor. Currently, mass spectrometry analysis is being performed to identify the specific cysteine residue/s that are palmitoylated to aid future studies. Taken together, these findings suggest inhibition of palmitoylation could be a novel target for treating prostate cancer driven by oncogenic c-Met.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2012
- Accession Number
- ADA569672
Entities
People
- David T. Coleman
Organizations
- Louisiana State University