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cAMP-dependent protein kinase is essential for hypoxia-mediated epithelial-mesenchymal transition, migration, and invasion in lung cancer cells

journal contribution
posted on 07.11.2013, 00:00 by Dooniya Shaikh, Qiyuan Zhou, Tianji Chen, Joyce Christina F. Ibe, Guofei Zhou, J. Usha Raj
Lung cancer is the leading cause of cancer-related death worldwide. Hypoxia is known to increase cancer cell migration and invasion. We have previously reported that hypoxia induces epithelial-mesenchymal transition (EMT) in lung cancer cells. However, it is unknown whether hypoxia promotes lung cancer cell migration and invasion via EMT and whether cyclic AMP (cAMP) dependent protein kinase (PKA) plays a role in this process. We found that hypoxia increased PKA activity and induced mRNA and protein expression of PKA catalytic subunit α (PKACA), and regulatory subunits R1A and R1B. Knockdown of HIF-1/2α prevented hypoxia-mediated induction of PKACA mRNA expression and PKA activity. Inhibition of PKA activity with chemical inhibitors prevented EMT induced by hypoxia and tumor growth factor β1. However, activation of PKA by forskolin and 8-Br-cAMP did not induce EMT. Furthermore, treatment with H89 and knockdown of PKACA prevented hypoxia-mediated, EMT, cell migration, and invasion, whereas overexpression of mouse PKACA rescued hypoxia-mediated migration and invasion in PKACA deficient cancer cells. Our results suggest that hypoxia enhances PKA activity by upregulating PKA gene expression in a HIF dependent mechanism and that PKA plays a key role in hypoxia-mediated EMT, migration, and invasion in lung cancer cells.

Funding

The work was supported in part by UIC Faculty Scholarship Support Program (GZ), the University of Illinois Cancer Center Pilot Subsidy Program (GZ), the Kabbes Scholarship for undergraduate research (DS).

History

Publisher Statement

NOTICE: this is the author’s version of a work that was accepted for publication in Cellular Signalling. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Cellular Signalling , [Vol 24, Issue 12, 2012] DOI: 10.1016/j.cellsig.2012.08.007

Publisher

Elsevier

Language

en_US

issn

1873-3913

Issue date

01/12/2012

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