Phosphodiesterase 10A: a novel target for selective inhibition of colon tumor cell growth and [beta]-catenin-dependent TCF transcriptional activity

• Published in: Oncogene Vol. 34; no. 12; p. 1499
• Main Authors: Li, N, Lee, K, Xi, Y, Zhu, B, Gary, B D, Ramírez-alcántara, V, Gurpinar, E, Canzoneri, J C, Fajardo, A, Sigler, S, Piazza, J T, Chen, X, Andrews, J, Thomas, M, Lu, W, Li, Y, Laan, D J, Moyer, M P, Russo, S, Eberhardt, B T, Yet, L, Keeton, A B, Grizzle, W E, Piazza, G A
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group 19.03.2015
• Subjects: Cells; Colon; Drug therapy; Inhibitor drugs; Tumorigenesis; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.94

The cyclic nucleotide phosphodiesterase 10A (PDE10) has been mostly studied as a therapeutic target for certain psychiatric and neurological conditions, although a potential role in tumorigenesis has not been reported. Here we show that PDE10 is elevated in human colon tumor cell lines compared with normal colonocytes, as well as in colon tumors from human clinical specimens and intestinal tumors from ApcMin/+ mice compared with normal intestinal mucosa, respectively. An isozyme and tumor-selective role of PDE10 were evident by the ability of small-molecule inhibitors and small interfering RNA knockdown to suppress colon tumor cell growth with reduced sensitivity of normal colonocytes. Stable knockdown of PDE10 by short hairpin RNA also inhibits colony formation and increases doubling time of colon tumor cells. PDE10 inhibition selectively activates cGMP/cGMP-dependent protein kinase signaling to suppress -catenin levels and T-cell factor (TCF) transcriptional activity in colon tumor cells.