β-catenin nuclear translocation in colorectal cancer cells is suppressed by PDE10A inhibition, cGMP elevation, and activation of PKG.

Kevin Lee,Joel Andrews,Gary A Piazza,Ashley S Lindsey,Bernard Gary,Nan Li,Adam B Keeton

doi:10.18632/oncotarget.6705

Kevin Lee, Joel Andrews + Show 5 more

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https://doi.org/10.18632/oncotarget.6705

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Abstract

Phosphodiesterase 10A (PDE10) is a cGMP and cAMP degrading PDE isozyme that is highly expressed in the brain striatum where it appears to play an important role in cognition and psychomotor activity. PDE10 inhibitors are being developed for the treatment of schizophrenia and Huntington's disease and are generally well tolerated, possibly because of low expression levels in most peripheral tissues. We recently reported high levels of PDE10 in colon tumors and that genetic silencing of PDE10 by siRNA or inhibition with small molecule inhibitors can suppress colon tumor cell growth with a high degree of selectivity over normal colonocytes (Li et al., Oncogene 2015). These observations suggest PDE10 may have an unrecognized role in tumorigenesis. Here we report that the concentration range by which the highly specific PDE10 inhibitor, Pf-2545920 (MP-10), inhibits colon tumor cell growth parallels the concentration range required to increase cGMP and cAMP levels, and activates PKG and PKA, respectively. Moreover, PDE10 knockdown by shRNA reduces the sensitivity of colon tumor cells to the growth inhibitory activity of Pf-2545920. Pf-2545920 also inhibits the translocation of β-catenin to the nucleus, thereby reducing β-catenin mediated transcription of survivin, resulting in caspase activation and apoptosis. PDE10 mRNA was also found to be elevated in colon tumors compared with normal tissues. These findings suggest that PDE10 can be targeted for cancer therapy or prevention whereby inhibition results in cGMP elevation and PKG activation to reduce β-catenin-mediated transcription of survival proteins leading to the selective apoptosis of cancer cells.

Highlights

Phosphodiesterase 10 (PDE10) was first identified in 1999 by three groups independently [1]–[3]
The majority of research being conducted on PDE10 is in the field of neurobiology where there is evidence that PDE10 inhibitors are effective in animal models of schizophrenia [7], [8] and in Huntington’s disease [9]
Human colon cancer cell lines were previously reported to have high levels of PDE10 compared with normal colonocytes and that treatment using selective PDE10 inhibitors can inhibit colon tumor cell growth

Summary

Introduction

Phosphodiesterase 10 (PDE10) was first identified in 1999 by three groups independently [1]–[3]. PDE10 is a dual substrate PDE that can hydrolyze both cyclic guanosine monophosphoate (cGMP) and cyclic adenosine monophosphate (cAMP). Unlike other PDE isozymes, PDE10 is expressed at high levels in the brain striatum but has limited expression in peripheral tissues in humans [4]. In the central nervous system PDE10 is known to mediate the responsiveness of striatal medium spiny neurons to dopaminergic transmission as shown by studies using PDE10A knockout mice [5]. There are two known isoforms of PDE10A in humans, PDE10A1 which is cytosolic, while PDE10A2 contains 10 extra amino acids at the N-terminal domain, consisting of a membrane binding domain and a protein kinase A (PKA) phosphorylation motif [6]. The majority of research being conducted on PDE10 is in the field of neurobiology where there is evidence that PDE10 inhibitors are effective in animal models of schizophrenia [7], [8] and in Huntington’s disease [9]

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