Abstract 42: Biological significance of the lipogenic enzyme acetyl-CoA carboxylase in the control of metastatic properties of murine and human transformed cells

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC In recent years, it has been determined that the fatty acid synthesis pathway is upregulated in several types of cancers of epithelial origin at both transcriptional and translational levels. Unlike normal cells, cancer cells rely on this pathway to provide the fatty acid precursors needed for synthesizing lipids that preferentially segregate into the liquid ordered microdomains of the plasma membrane. Acetyl-CoA carboxylase (ACC) is the ATP dependent and rate limiting step of fatty acid synthesis and catalyzes the carboxylation of acetyl-CoA to malonyl-CoA. Interestingly, overexpression of this enzyme increases with severity of breast cancer patient samples and cell lines, indicating a possible role for ACC in the metastatic process. Preliminary findings from our lab indicate that ACC is important for the proteolytic invasion and migration of transformed cells independently of cell death. Moreover, ACC is critical for formation of F-actin rich membrane structures known as podosomes, which have been implicated in the metastatic process in recent years. Restoration of podosomes in cells with ACC inhibition was achieved with the addition of the soluble fatty acid, C18:1 (oleate). In contrast, inhibition of the fatty acid synthetic enzyme, fatty acid synthase (FASN), or the Δ9 desaturase, stearoyl-CoA desaturase 1 (SCD-1), does not affect podosome formation. However, inhibition of FASN resulted in attenuated proteolytic invasion and migration of transformed cells with a phenotype similar to cells with ACC inhibition although not quite to the same degree. In addition to regulation at transcriptional and translational levels, ACC activity is also regulated by phosphorylation/dephosphorylation by AMP activated protein kinase (AMPK). Decreased ACC phosphorylation at serine 79 (S79) has been shown to correlate with increased disease severity and reduced disease free survival of lung adenocarcinoma patients. This indicates that the phosphorylation status of ACC may be an important mechanism that cancer cells manipulate to successfully achieve metastasis. Therefore, induction of phosphorylation, and inactivation of ACC, either by activation of AMPK or by direct mutation of S79 may be sufficient to reduce invasion and migration of cancer cells. Taken together, investigating ACC phosphorylation status and analyzing the resulting phenotype will advance the mechanistic understanding of how cancer cells metastasize and possibly provide new therapeutic avenues to explore in the treatment of disseminated disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 42.