Oncotarget

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Phosphodiesterase 10A is overexpressed in lung tumor cells and inhibitors selectively suppress growth by blocking β-catenin and MAPK signaling

Bing Zhu, Ashley Lindsey, Nan Li, Kevin Lee, Veronica Ramirez-Alcantara, Joshua C. Canzoneri, Alexandra Fajardo, Luciana Madeira da Silva, Meagan Thomas, John T. Piazza, Larry Yet, Brian T. Eberhardt, Evrim Gurpinar, Dennis Otali, William Grizzle, Jacob Valiyaveettil, Xi Chen, Adam B. Keeton and Gary A. Piazza _

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Oncotarget. 2017; 8:69264-69280. https://doi.org/10.18632/oncotarget.20566

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Abstract

Bing Zhu1, Ashley Lindsey1, Nan Li2, Kevin Lee1, Veronica Ramirez-Alcantara1, Joshua C. Canzoneri1, Alexandra Fajardo1, Luciana Madeira da Silva1, Meagan Thomas1, John T. Piazza1, Larry Yet3, Brian T. Eberhardt3, Evrim Gurpinar4, Dennis Otali5, William Grizzle5, Jacob Valiyaveettil1, Xi Chen1, Adam B. Keeton1 and Gary A. Piazza1

1 Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA

2 Department of Biochemistry and Molecular Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA

3 Department of Chemistry, University of South Alabama, Mobile, Alabama, USA

4 Department of Pharmacology, The University of Alabama at Birmingham, Birmingham, Alabama, USA

5 Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama, USA

Correspondence to:

Gary A. Piazza, email:

Bing Zhu, email:

Keywords: lung cancer, PDE10, PKG, cGMP, PQ10

Received: June 30, 2017 Accepted: August 04, 2017 Published: August 27, 2017

Abstract

Phosphodiesterase 10A (PDE10) is a cyclic nucleotide (e.g. cGMP) degrading enzyme highly expressed in the brain striatum where it plays an important role in dopaminergic neurotransmission, but has limited expression and no known physiological function outside the central nervous system. Here we report that PDE10 mRNA and protein levels are strongly elevated in human non-small cell lung cancer cells and lung tumors compared with normal human airway epithelial cells and lung tissue, respectively. Genetic silencing of PDE10 or inhibition by small molecules such as PQ10 was found to selectively inhibit the growth and colony formation of lung tumor cells. PQ10 treatment of lung tumor cells rapidly increased intracellular cGMP levels and activated cGMP-dependent protein kinase (PKG) at concentrations that inhibit lung tumor cell growth. PQ10 also increased the phosphorylation of β-catenin and reduced its levels, which paralleled the suppression of cyclin D1 and survivin but preceded the activation of PARP and caspase cleavage. PQ10 also suppressed RAS-activated RAF/MAPK signaling within the same concentration range and treatment period as required for cGMP elevation and PKG activation. These results show that PDE10 is overexpressed during lung cancer development and essential for lung tumor cell growth in which inhibitors can selectively induce apoptosis by increasing intracellular cGMP levels and activating PKG to suppress oncogenic β-catenin and MAPK signaling.


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