Phosphodiesterase 10A: a novel target for selective inhibition of colon tumor cell growth and β-catenin-dependent TCF transcriptional activity View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-03

AUTHORS

Nan Li, Kevin Lee, Yaguang Xi, Bing Zhu, Bernard D. Gary, Verónica Ramírez-Alcántara, Evrim Gurpinar, Joshua C. Canzoneri, Alexandra Fajardo, Sara Sigler, John T. Piazza, Xi Chen, Joel Andrews, Meagan Thomas, Wenyan Lu, Yonghe Li, Danuel J. Laan, Mary P. Moyer, Suzanne Russo, Brian T. Eberhardt, Larry Yet, Adam B. Keeton, William E. Grizzle, Gary A. Piazza

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. More... »

PAGES

1499

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/onc.2014.94

DOI

http://dx.doi.org/10.1038/onc.2014.94

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1044496869

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/24704829


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