1. Phosphodiesterase 10A: a novel target for selective inhibition of colon tumor cell growth and β-catenin-dependent TCF transcriptional activity
- Author
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Kevin Lee, Alexandra M. Fajardo, Bernard D. Gary, Suzanne Russo, Evrim Gurpinar, Mary Pat Moyer, Veronica Ramirez-Alcantara, John T. Piazza, Xi Chen, Sara Sigler, Adam B. Keeton, Danuel J. Laan, Wenyan Lu, Meagan Thomas, Yonghe Li, Yaguang Xi, Joshua C. Canzoneri, Joel Andrews, Larry Yet, Gary A. Piazza, Nan Li, William E. Grizzle, Brian T. Eberhardt, and Bing Zhu
- Subjects
Cancer Research ,Small interfering RNA ,Transcription, Genetic ,Phosphodiesterase Inhibitors ,colorectal cancer ,Biology ,medicine.disease_cause ,Article ,Small hairpin RNA ,Growth factor receptor ,Intestinal mucosa ,Cell Line, Tumor ,Genetics ,medicine ,Humans ,RNA, Small Interfering ,Molecular Biology ,beta Catenin ,Cell Proliferation ,Gene knockdown ,Phosphoric Diester Hydrolases ,PKG ,Phosphodiesterase ,β-catenin ,Cell cycle ,HCT116 Cells ,Molecular biology ,3. Good health ,Gene Expression Regulation, Neoplastic ,cGMP ,HEK293 Cells ,phosphodiesterase 10 ,Gene Knockdown Techniques ,Colonic Neoplasms ,TCF Transcription Factors ,Carcinogenesis ,HT29 Cells ,Signal Transduction - Abstract
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 Apc(Min/+) 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 β-catenin levels and T-cell factor (TCF) transcriptional activity in colon tumor cells. Conversely, ectopic expression of PDE10 in normal and precancerous colonocytes increases proliferation and activates TCF transcriptional activity. These observations suggest a novel role of PDE10 in colon tumorigenesis and that inhibitors may be useful for the treatment or prevention of colorectal cancer.
- Published
- 2014