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

Oncogene volume 34, pages 1499–1509 (2015)Cite this article

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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 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 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.

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Acknowledgements

We thank Dr Graeme Bolger for critical reading of the manuscript. We also thank Dr Marian from Medical University Vienna, Austria for the generous gift of LT97 adenoma cell line and Dr Dan Dixon from University of Kansas Cancer Center for providing specimens from the ApcMin/+ mouse model. We are also grateful to Dr Darren Browning from Georgia Regents University Cancer Center for providing the CTNNB1 luciferase reporter construct. This work was supported by National Institutes of Health Grants, 1R01CA131378, 1R01CA148817 and 1R01CA155638 to GAP.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA

    N Li

  2. Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA,

    K Lee, Y Xi, B Zhu, B D Gary, V Ramírez-Alcántara, J C Canzoneri, A Fajardo, S Sigler, J T Piazza, X Chen, J Andrews, M Thomas, S Russo, A B Keeton & G A Piazza

  3. Department of Pharmacology and Toxicology, The University of Alabama at Birmingham, Birmingham, AL, USA

    E Gurpinar

  4. Drug Discovery Division, Southern Research Institute, Birmingham, AL, USA

    W Lu & Y Li

  5. School of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA

    D J Laan

  6. INCELL Corporation LLC, San Antonio, TX, USA

    M P Moyer

  7. Department of Chemistry, University of South Alabama, Mobile, AL, USA

    B T Eberhardt & L Yet

  8. Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, USA

    W E Grizzle

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Correspondence to G A Piazza.

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MPM has ownership interest (including patents) in INCELL Corporation. The remaining authors declare no conflict of interest.

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Li, N., Lee, K., Xi, Y. et al. Phosphodiesterase 10A: a novel target for selective inhibition of colon tumor cell growth and β-catenin-dependent TCF transcriptional activity. Oncogene 34, 1499–1509 (2015). https://doi.org/10.1038/onc.2014.94

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