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.

Sevoflurane suppresses hypoxia-induced growth and metastasis of lung cancer cells via inhibiting hypoxia-inducible factor-1α

“…Numerous studies documented that the hypoxia microenvironment was able to enhance tumor progression [9,15]. A growing body of evidence demonstrated that there is a high correlation between hypoxia and lung cancer metastasis and poor prognosis [16,17].…”

“…Accumulating evidence has indicated that the hypoxia microenvironment promotes the growth and metastasis of lung cancer cells [8,9]. One-lung ventilation (OLV) is a standard anesthesia practice that was widely used in lung cancer resection surgery.…”

High throughput molecular profiling reveals differential mutation patterns in intrahepatic cholangiocarcinomas arising in chronic advanced liver diseases

“…The subsequent increase in cAMP levels induces the production of protein kinase A, which is essential for the hypoxia-mediated epithelialmesenchymal transition, as well as the migration and invasion of these tumorigenic cells in lung cancer. 28 Therefore, intrahepatic cholangiocarcinoma patient with this mutation may be investigated in a clinical trial for targeted therapy with protein kinase A inhibitors developed for that purpose.…”

Mixed-effects model of epithelial–mesenchymal transition reveals rewiring of signaling networks

“…Alternate pathways for HSP27 phosphorylation at Ser78 include the Protein Kinase A (PKA) pathway [41]. PKA has been implicated in hypoxia-mediated EMT in lung cancer [42]. …”