Abstract 5390: Chemical disruption of Wnt protein fatty acylation as an anti-cancer therapeutic strategy.

Abstract

Abstract The secreted Wnt signaling molecules are associated with a broad range of cancers and represent high priority therapeutic targets. Recently identified small molecules that disrupt Wnt biosynthesis by disabling the extracellular acyltransferase Porcupine (Porcn) form the basis of a novel targeted anti-cancer therapeutic strategy. Porcn is a founding member of a sixteen gene family known as Membrane-Bound O-Acyltransferases (MBOATs) that likely control the production of a broad range of disease-relevant signaling molecules. A deeper understanding of the chemical-protein interaction that confers Porcn inhibitors with selectivity would facilitate the engineering of improved Porcn inhibitors and molecules with activity against other MBOAT family members. Using synthetic fatty acyl analogues that allow direct labeling of Wnt proteins and chemical inhibitors of fatty acid metabolic enzymes, we have uncovered that Porcn utilizes a monounsaturated 16-carbon fatty acid as a substrate. Chemical disruption of stearoyl-CoA desturase (SCD) that converts palmitate to palmitoleate blocks Wnt protein production and activity thus revealing another potential chemical strategy for inhibiting Wnt-dependent cancerous growth. The inability of several other Porcn family members with known protein substrates to utilize palmitoleate may account for the selectivity of Porcn classes of inhibitors. Our study expands the number of drug targets to include those enzymes that control the production of secreted signaling molecules and reveals a direct influence of cellular metabolic status on coordinated and cancerous cell growth regulation. Citation Format: Rubina Tuladhar, Lawrence Lum. Chemical disruption of Wnt protein fatty acylation as an anti-cancer therapeutic strategy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5390. doi:10.1158/1538-7445.AM2013-5390