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

Dooniya Shaikh,Qiyuan Zhou,Tianji Chen,Joyce Christina F Ibe,J Usha Raj,Guofei Zhou

doi:10.1016/j.cellsig.2012.08.007

Dooniya Shaikh, Qiyuan Zhou + Show 4 more

Open Access

https://doi.org/10.1016/j.cellsig.2012.08.007

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Journal: Cellular Signalling	Publication Date: Aug 27, 2012
Citations: 78	License type: cc-by

Affiliation: University of Illinois at Chicago

Abstract

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.

Highlights

Lung cancer is the leading cause of cancer-related death worldwide, with adenocarcinoma as the most common subtype accounting for almost half of all lung cancers [1, 2]
Our results suggest that hypoxia enhances protein kinase (PKA) activity by upregulating PKA gene expression in a HIF dependent mechanism and that PKA plays a key role in hypoxia-mediated epithelial-mesenchymal transition (EMT), migration, and invasion in lung cancer cells
Our results suggest that hypoxia-mediated upregulation of PKA requires HIF and knockdown of PKA α catalytic subunit prevents hypoxia-induced lung cancer cell migration and invasion, suggesting that PKA plays a critical role in lung cancer progression via EMT and therapies that target PKA signaling pathway may provide novel means of treatment of patients with lung cancer

Summary

Introduction

Lung cancer is the leading cause of cancer-related death worldwide, with adenocarcinoma as the most common subtype accounting for almost half of all lung cancers [1, 2]. Lung cancer cells proliferate rapidly and their growth exceeds the oxygen supply available to the cells, creating regions where there is low oxygen tension (hypoxia) [3, 4]. Cancer cells are able to adapt to hypoxia and gain increased potential for migration, invasion, and metastasis, which is the main cause of cancer related death [3]. Invasion and metastasis of cancer cells involves characteristic changes in the cell that are similar to those during epithelial-mesenchymal transition (EMT). EMT is a molecular and cellular process during which epithelial cells lose cell-cell contact and apico-basal polarity and acquire mesenchymal and migratory properties [5, 6].

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