Abstract 1773: Phosphodiesterase 10A: A novel target for selective inhibition of colon tumor cell growth and Wnt/β-catenin signaling

Abstract

Abstract The cyclic nucleotide phosphodiesterase10A (PDE10) has been studied as a therapeutic target for certain psychiatric and neurological conditions, although a potential role in tumorigenesis has not been reported. Here we report that PDE10 is elevated in human colon tumor cell lines compared with normal colonocytes. Similarly, PDE10 is elevated in colon tumors from human clinical specimens as well as intestinal tumors from the ApcMin/+ mouse model compared with non-involved tissue or normal intestinal mucosa, respectively. An isozyme and tumor-selective role of PDE10 was evident by the ability of specific inhibitors and siRNA knockdown to suppress colon tumor cell growth without significantly affecting the growth of normal colonocytes. Stable knockdown of PDE10 by shRNA also inhibits colony formation and increases doubling time of colon tumor cells. Inhibition of PDE10 results in the selective activation of cGMP/PKG signaling in colon tumor cells to suppress β-catenin levels and T-cell factor (TCF) transcriptional activity. Conversely, ectopic expression of PDE10 in normal and precancerous colonocytes increases proliferation and activates TCF transcriptional activity. These observations demonstrate that PDE10 is essential for colon tumor cell growth and suggest that inhibitors may have therapeutic potential for the treatment or prevention of colorectal cancer. Citation Format: Nan Li, Kevin Lee, Yaguang Xi, Bing Zhu, Bernary D. Gary, Verónica Ramírez-Alcántara, Evrim Gurpinar, Joshua C. Canzoneri, Alexandra Fajardo, Sara Sigler, John T. Piazza, Xi Chen, Joel Andrews, Wenyan Lu, Yonghe Li, Suzanne Russo, Larry Yet, Adam B. Keeton, William E. Grizzle, Gary A. Piazza. Phosphodiesterase 10A: A novel target for selective inhibition of colon tumor cell growth and Wnt/β-catenin signaling. [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 1773. doi:10.1158/1538-7445.AM2014-1773