title: 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.
authors.affiliation: a Department of Cell Stress Biology ; Roswell Park Cancer Institute ; Buffalo , NY USA.
authors.forename: Evan R
authors.initials: ER
authors.lastname: Zynda
authors.forename: Vitaliy
authors.initials: V
authors.lastname: Matveev
authors.forename: Michael
authors.initials: M
authors.lastname: Makhanov
authors.forename: Alexander
authors.initials: A
authors.lastname: Chenchik
authors.forename: Eugene S
authors.initials: ES
authors.lastname: Kandel
mesh_terms: D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000077143:Docetaxel; D006801:Humans; D008297:Male; D017239:Paclitaxel / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D043823:Taxoids / Q000494:pharmacology*
chemical_list: D001952:Bridged-Ring Compounds; D047428:Protein Kinase Inhibitors; D043823:Taxoids; D000077143:Docetaxel; C080625:taxane; D017868:Cyclic AMP-Dependent Protein Kinases; D017239:Paclitaxel
keywords: PKA, Protein kinase A (aka cAMP-Dependent Protein Kinase); PPKAR2A, cAMP-Dependent Protein Kinase Regulatory Subunit RII Alpha; docetaxel; doxorubicin; forward genetics; insertional mutagenesis; miRNA, micro RNA; paclitaxel; prostate cancer; protein kinase A; shRNA, short hairpin RNA; vincristine