Abstract 1216: c-Met protein expression is regulated by palmitoylation in prostate cancer cells
Authors: Coleman David Thomas , Cardelli James A. 
Published: August 2012

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 androgen-independence and metastasis. Organ-confined PCa is often 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. Numerous bodies of evidence strongly link aberrant c-Met signaling with causation and/or progression of prostate cancer. Overexpression of c-Met can lead to activation in a ligand-independent manner and has been identified as a common mechanism of resistance to RTK-targeted therapy. In addition, multiple reports have identified the enzyme fatty acid synthase (FASN) as being commonly overexpressed in prostate cancer, and that this aberrant expression is an early event that becomes more pronounced with aggressive androgen-independent and metastatic disease. FASN is the sole enzyme responsible for de novo synthesis of the 16-carbon saturated fatty acid palmitate. In cancer, de novo lipids are more selectively partitioned into lipid rafts as phospholipids as well as utilized for post-translational acyl-modifications of signaling proteins. Previous findings have led us to identify a novel mechanism by which FASN activity regulates c-Met expression. Our work has determined that inhibition or shRNA knockdown of FASN results in a post-translational downregulation of already synthesized c-Met protein. This downregulation is prevented by the addition of exogenous palmitate. Here we provide evidence that inhibition of palmitoylation, using the palmitate analog 2-bromopalmitate, lowers total c-Met levels. 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, our findings suggest the 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 have provided evidence suggesting c-Met itself is palmitoylated. From these data, we hypothesize that c-Met requires palmitoylation along a biosynthetic route to promote its stability and trafficking to the cell surface. In the absence of palmitoylation, c-Met accumulates within the Golgi and is disposed of through a yet to be determined degradation pathway. Our findings potentially reveal a novel mechanism for restricting the expression of c-Met as a means of preventing prostate cancer invasion and metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1216. doi:1538-7445.AM2012-1216