title: Type 10 soluble adenylyl cyclase is overexpressed in prostate carcinoma and controls proliferation of prostate cancer cells.
abstract: cAMP signaling plays an essential role in modulating the proliferation of different cell types, including cancer cells. Until now, the regulation of this pathway was restricted to the transmembrane class of adenylyl cyclases. In this study, significant overexpression of soluble adenylyl cyclase (sAC), an alternative source of cAMP, was found in human prostate carcinoma, and therefore, the contribution of this cyclase was investigated in the prostate carcinoma cell lines LNCaP and PC3. Suppression of sAC activity by treatment with the sAC-specific inhibitor KH7 or by sAC-specific knockdown mediated by siRNA or shRNA transfection prevented the proliferation of prostate carcinoma cells, led to lactate dehydrogenase release, and induced apoptosis. Cell cycle analysis revealed a significant rise in the G(2) phase population 12 h after sAC inhibition, which was accompanied by the down-regulation of cyclin B(1) and CDK1. sAC-dependent regulation of proliferation involves the EPAC/Rap1/B-Raf signaling pathway. In contrast, protein kinase A does not play a role. In conclusion, this study suggests a novel sAC-dependent signaling pathway that controls the proliferation of prostate carcinoma cells.
authors.affiliation: Department of Clinical Pharmacology, Ruhr University Bochum, 44801 Bochum, Germany.
authors.forename: Jan-Paul
authors.initials: JP
authors.lastname: Flacke
authors.forename: Hanna
authors.initials: H
authors.lastname: Flacke
authors.forename: Avinash
authors.initials: A
authors.lastname: Appukuttan
authors.forename: Rein-Jüri
authors.initials: RJ
authors.lastname: Palisaar
authors.forename: Joachim
authors.initials: J
authors.lastname: Noldus
authors.forename: Brian D
authors.initials: BD
authors.lastname: Robinson
authors.forename: H Peter
authors.initials: HP
authors.lastname: Reusch
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Zippin
authors.forename: Yury
authors.initials: Y
authors.lastname: Ladilov
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints; D055785:Gene Knockdown Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008938:Mitosis; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D021381:Protein Transport; D012995:Solubility; D013347:Subcellular Fractions / Q000201:enzymology
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; C116122:RAPGEF3 protein, human; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C579271:ADCY10 protein, human; D000262:Adenylyl Cyclases