Possible mechanism of CCL2-induced Akt activation in prostate cancer cells.
C-C chemokine ligand 2 (CCL2) is a chemokine that has been demonstrated to play a pivotal role in prostate cancer tumorigenesis and metastasis. These effects are mediated by the ligand binding to the G protein-coupled receptor (GPCR) C-C chemokine receptor 2 (CCR2). It has recently been demonstrated that CCL2 increases Akt phosphorylation in prostate cancer cells, and prevents prostate cancer cells from autophagic death through activation of Akt pathway. The purpose of this study was to determine the mechanism by which CCL2 activates Akt in prostate cancer PC-3 cell line. CCL2-induced phosphorylation of Akt was inhibited by pertussis toxin and the adenylyl cyclase inhibitor SQ22536. Akt phosphorylation was promoted by prior treatment with cholera toxin. The results suggest that CCL2-induced Akt phosphorylation is mediated by the Galphai complex and adenylyl cyclase. This is the first study that demonstrates a direct involvement of adenylyl cyclase in CCL2-induced Akt phosphorylation.
Mizutani
Kosuke
K
Departments of Internal Medicine and Urology, University of Michigan School of Medicine, 7308 CCC 1500 E. Medical Center Drive, Ann Arbor, MI 48109-5946, USA.
Roca
Hernan
H
Varsos
Zachary
Z
Pienta
Kenneth J
KJ
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000378:metabolism*; D002772:Cholera Toxin / Q000494:pharmacology; D006801:Humans; D008297:Male; D037342:Pertussis Toxin / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012844:Sincalide / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000067956:Adenylyl Cyclase Inhibitors; D000276:Adjuvants, Immunologic; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D002772:Cholera Toxin; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases; D020741:rho GTP-Binding Proteins; D000262:Adenylyl Cyclases; D012844:Sincalide