Abstract
Abstract Lung cancer is the leading cause of cancer death worldwide. Recent data suggest that cyclic nucleotide phosphodiesterases (PDEs) are relevant in various cancer pathologies. Here, we elucidate the pathophysiological role of PDE4 and its therapeutic prospects in lung cancer. We exposed 10 different non-small cell lung cancer cell lines (adenocarcinoma, squamous, and large cell carcinoma) to hypoxia and assessed the expression and activity of PDE4 by quantitative real-time PCR, immunocytochemistry, western blotting, and PDE activity assays. Expression and activity of distinct PDE4 isoforms (PDE4A and PDE4D) increased in response to hypoxia in eight of the studied cell lines. Furthermore, we determined various potential hypoxia-responsive elements (HRE) in PDE4A and PDE4D. Silencing of hypoxia-inducible factor subunits (HIF1A and HIF2) by siRNA reduced hypoxic induction of PDE4A and PDE4D. Vice versa, using a PDE4 inhibitor (PDE4i), a cAMP-elevating agent, cAMP analogs, PKA activator/inhibitor, and EPAC activator, we demonstrated that PDE4-cAMP-PKA/EPAC axis regulates HIF signaling as measured by HRE reporter gene assay and expression of HIF target genes (LDHA, PDK1, VEGFA). Notably, PDE4i or PDE4A-/PDE4D-selective siRNA reduced human lung tumor cell proliferation in vitro and colony formation and altered the expression of cell-cycle regulators. Moreover, PDE4i treatment reduced hypoxia-induced VEGF secretion in human cells. In vivo, PDE4i inhibited tumor xenograft growth in athymic nude mice by altering proliferation and angiogenesis. Collectively, our findings suggest that PDE4 is overexpressed in lung cancer, exerts crosstalk with HIF pathways, and promotes lung cancer progression; thus, PDE4 may represent a therapeutic target for lung cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1839. doi:1538-7445.AM2012-1839
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.