Protein kinase A type II-α regulatory subunit regulates the response of prostate cancer cells to taxane treatment

Abstract

In the last decade taxane-based therapy has emerged as a standard of care for hormone-refractory prostate cancer. Nevertheless, a significant fraction of tumors show no appreciable response to the treatment, while the others develop resistance and recur. Despite years of intense research, the mechanisms of taxane resistance in prostate cancer and other malignancies are poorly understood and remain a topic of intense investigation. We have used improved mutagenesis via random insertion of a strong promoter to search for events, which enable survival of prostate cancer cells after Taxol exposure. High-throughput mapping of the integration sites pointed to the PRKAR2A gene, which codes for a type II-α regulatory subunit of protein kinase A, as a candidate modulator of drug response. Both full-length and N-terminally truncated forms of the PRKAR2A gene product markedly increased survival of prostate cancer cells lines treated with Taxol and Taxotere. Suppression of protein kinase A enzymatic activity is the likely mechanism of action of the overexpressed proteins. Accordingly, protein kinase A inhibitor PKI (6-22) amide reduced toxicity of Taxol to prostate cancer cells. Our findings support the role of protein kinase A and its constituent proteins in cell response to chemotherapy.

A Novel Platelet-Related Gene Signature for Predicting the Prognosis of Triple-Negative Breast Cancer

“…Previous studies have shown that PRKAR2A deficiency predisposes patients to hematopoietic malignancies ( Saloustros et al, 2015 ). In addition, PRKAR2A has been found to regulate the response of cancer cells to chemotherapy, which might be the reason why our established model helped predict the curative effect of neoadjuvant therapy in TNBC patients ( Zynda et al, 2014 ). The thromboxane A2 receptor (TBXA2R) is a specific coordinator of the T prostanoid receptor (TPR), which is associated with the platelet activity.…”

The PDE4DIP-AKAP9 axis promotes lung cancer growth through modulation of PKA signalling

“…While germline and somatic mutations in the genes encoding the PKA R subunits have been characterized, little is known about the biological functions of aberrant PKA RIIα expression in human tumours [40]. Overexpression of PKA RIIα has been shown to increase the survival of prostate cancer cells treated with Taxol [41]. In HCC cells, anchoring of PKA RIIα at the Golgi is required for e cient and coordinated delivery of proteins and sphingolipids to the apical membrane [42].…”

Bifunctional Ligands for Inhibition of Tight-Binding Protein–Protein Interactions

“…Continuous production of cAMP can lead to activation of PKA dissociated by the PKA:AKAP inhibitor, releasing PKAc for substrate phosphorylation events in remote locations. The inadequate control of activity by regulatory subunit is seen in the PKArIIα overexpressing prostate cancer cells, in which application of PKI­(6–22) peptide further improved the cell survival . Considering that numerous AKAPs scaffold both AC and PKA, the application of ARCs emerge as a novel tool for studying the underlying mechanism of this important signaling pathway.…”