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

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.

• Authors: Dooniya Shaikh, Qiyuan Zhou, Tianji Chen, Joyce Christina F Ibe, J Usha Raj, Guofei Zhou
• Journal: Cellular signalling (Cell Signal) Vol. 24 Issue 12 Pg. 2396-406 (Dec 2012) ISSN: 1873-3913 [Electronic] England
• PMID: 22954688 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Hypoxia-Inducible Factor 1, alpha Subunit
• Isoquinolines
• RNA, Small Interfering
• Sulfonamides
• Transforming Growth Factor beta1
• endothelial PAS domain-containing protein 1
• Colforsin
• 8-Bromo Cyclic Adenosine Monophosphate
• Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
• Cyclic AMP-Dependent Protein Kinases
• N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide

Topics

• 8-Bromo Cyclic Adenosine Monophosphate (pharmacology)
• Animals
• Basic Helix-Loop-Helix Transcription Factors (antagonists & inhibitors, genetics, metabolism)
• Cell Hypoxia
• Cell Line, Tumor
• Cell Movement (drug effects)
• Colforsin (pharmacology)
• Cyclic AMP-Dependent Protein Kinase Catalytic Subunits (antagonists & inhibitors, genetics, metabolism)
• Cyclic AMP-Dependent Protein Kinases (genetics, metabolism)
• Epithelial-Mesenchymal Transition (drug effects)
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, genetics, metabolism)
• Isoquinolines (pharmacology)
• Lung Neoplasms (metabolism, pathology)
• Mice
• RNA Interference
• RNA, Small Interfering (metabolism)
• Sulfonamides (pharmacology)
• Transforming Growth Factor beta1 (pharmacology)
• Up-Regulation (drug effects)