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

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.

Discovery of Novel Agents on Spindle Assembly Checkpoint to Sensitize Vinorelbine-Induced Mitotic Cell Death against Human Non-Small Cell Lung Cancers

“…YL-9, by itself, did not affect the cell proliferation ( Figure S1 ), survival ( Figure 2 and Figure S2 ) and cell cycle progression ( Figure 3 A). The sensitization activity of YL-9 on vinorelbine-induced effect was independent of the suppression of PDE5 because the experiments were performed in NCI-H460, a cell line with low PDE5 expression [ 22 ]. Furthermore, YL-9 displayed equal sensitization activity to sildenafil in vinorelbine-induced effects, although its anti-PDE5 activity was 167 times less than that of sildenafil.…”

“…NCI-H460 is a good cell model in studying anti-NSCLC research as the cells may harbor stem-like cells in readily forming anchorage-independent floating spheres, displaying high proliferative potential [21]. Furthermore, NCI-H460 is the cell line showing the least expression of PDE5 among various NSCLC cell lines [22] and enables the study of PDE5-independent signaling pathways in the present work. YL-9 exhibited similar potency to sildenafil in sensitizing vinorelbine-induced inhibition of cell proliferation in NCI-H460 cells using sulforhodamine B (SRB) assay.…”

NSAIDs and Cancer Resolution: New Paradigms beyond Cyclooxygenase

“…Sulindac and its derivatives highlight the involvement of the cGMP/PDE/PKG signaling pathway in cancer. PDE5 promotes tumorigenesis and is overexpressed in tumors of the colon, lung, and breast [95,[238][239][240]. Sulindac sulfide inhibited PDE5, resulting in higher intracellular cGMP levels, thus activating protein kinase G (PKG) [95,96].…”

cGMP: a unique 2nd messenger molecule – recent developments in cGMP research and development

“…Recent studies showed that PDE10A expression is upregulated in certain cancer models suggesting that PDE10Amediated signaling is involved in tumor cell growth (Zhu et al 2017). New PDE10A-inhibiting lead compounds that do not cross the blood brain barrier are being developed for cancer treatment (Gary Piazza, South Alabama).…”