Role of stimulatory guanine nucleotide binding protein (GSalpha) in proliferation of PC-3M prostate cancer cells.
Previous studies have shown that calcitonin-like immunoreactive substances are secreted by primary prostate cells. Furthermore, exogenously added calcitonin stimulates proliferation of androgen-responsive LnCaP cells. To examine the possible effect of calcitonin on growth of invasive prostate cancer cells, we tested its effects on proliferation of PC-3M cells. Calcitonin stimulated DNA synthesis of PC-3M cells in a dose-dependent fashion, and also stimulated adenylyl cyclase and protein kinase C activities. To further delineate the role of these signaling cascades in proliferation of PC-3M prostate cancer cells, we selectively activated these pathways by transfecting cDNAs expressing constitutively active forms of either Gsalpha (Gsalpha-QL) or Gqalpha (Gqalpha-QL). cDNAs expressing wild-type forms of G-proteins (Gsalpha-WT and Gqalpha-WT) were used as vehicle controls. Gqalpha-QL transfectants exhibited growth inhibition and terminal differentiation. Those expressing Gsalpha-QL exhibited a dramatic increase in growth rate. Gsalpha-QL transfectants displayed an almost 3-fold increase in [3H]-thymidine incorporation and over a 4-fold increase in growth rate when compared with parental PC-3M cells or those expressing wild-type Gsalpha (Gsalpha-WT). The growth-promoting action of Gsalpha-QL could not be mimicked by either 8-bromo cAMP or forskolin. However, nifedipine, a calcium channel antagonist, potently and selectively inhibited DNA synthesis in Gsalpha-QL transfectants. These results suggest that the growth-promoting actions of Gsalpha on PC-3M cells may be mediated by nifedipine-sensitive proliferative events.
Chien
J
J
Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, USA.
Shah
G V
GV
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D015153:Blotting, Western; D002116:Calcitonin / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism* / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000378:metabolism* / Q000502:physiology*; D006801:Humans; D008297:Male; D009543:Nifedipine / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D002116:Calcitonin; D014700:Verapamil; D000242:Cyclic AMP; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D019205:GTP-Binding Protein alpha Subunits, Gs; D000262:Adenylyl Cyclases; D009543:Nifedipine