Abstract 5301: Rescuing cell polarity with small molecule inhibitors of de-palmitoylation

Abstract

Abstract Protein palmitoylation is a unique post-translational modification required for the membrane anchoring and trafficking of numerous regulatory proteins that play key roles in cell growth, polarity, and signaling. Using a pulse-chase palmitoylation proteomics approach, we identified the tumor suppressor Scrib as the most dynamic, enzymatically regulated palmitoylated protein in malignant cells. Scrib localizes at the basolateral membrane where it regulates epithelial cell apical-basolateral polarity, junctional integrity, proliferation, and metastasis. Loss of Scrib at the plasma membrane cooperates with oncogenic Ras or Myc overexpression to drive tumor formation, promote epidermal to mesenchymal transition (EMT), and bypass contact inhibition. Interestingly, overexpression of Snail in polarized cells eliminates Scrib membrane localization. We recently reported a class of in vivo active small selective inhibitors of the acyl protein thioesterases APT1 and APT2. Addition of a small molecule APT2 inhibitor restores Scrib membrane localization and enhances E-Cadherin expression, overcoming Snail-mediated repression of E-cad. These findings suggest that thioesterases, predominantly APT2 more than APT1, regulate the palmitoylation of cell polarity proteins, and highlight a strategy to attenuate oncogenic signaling and restore cell polarity pathways in malignant cells. Citation Format: Jeannie L. Hernandez, Dahvid Davda, Jaimeen Majmudar, Kristin J. Labby, Margery Gang, Sirisha Pasupuleti, Makoto Seita, Brent R. Martin. Rescuing cell polarity with small molecule inhibitors of de-palmitoylation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5301. doi:10.1158/1538-7445.AM2014-5301