Src family kinase oncogenic potential and pathways in prostate cancer as revealed by AZD0530.
Prostate cancer is the most frequently diagnosed cancer in American men. We have previously demonstrated that Src mediates androgen-independent proliferation in prostate cancer. We sought to investigate the Src-mediated oncogenic pathways and tumor biology using AZD0530, a novel Src family kinase/Abl dual-kinase inhibitor that is entering phase II clinical trials. We show that while both Src and Abl are expressed in all prostate cancer cell lines, Src but not Abl is activated in the prostate. Furthermore, Src activation is inhibited by AZD0530 in a rapid and dose-dependent manner. We show that Src mediates cell proliferation in DU145 and PC3 cells at the G1 phase of cell cycle. Src inhibition resulted in decreased binding of beta-catenin to the promoters of G1 phase cell cycle regulators cyclin D1 and c-Myc. C-Myc may also be regulated at the protein level by extracellular signal-regulated kinase 1/2 and GSK3beta. Cell motility factors focal adhesion kinase, p130CAS and paxillin activation in DU145 and PC3 cells were also inhibited. Administration of AZD0530 in mice reduced orthotopic DU145 xenograft growth by 45%. We have further delineated the Src-mediated oncogenic growth and migration pathways in prostate cancer and established mechanistic rationale for Src inhibition as novel therapy in the treatment of prostate cancer.
Chang
Y-M
YM
Department of Urology, University of California at Davis, Sacramento, CA 95817, USA.
Bai
L
L
Liu
S
S
Yang
J C
JC
Kung
H-J
HJ
Evans
C P
CP
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D052117:Benzodioxoles / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D056741:Cyclin D; D016213:Cyclins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D012097:Repressor Proteins / Q000378:metabolism; D013997:Time Factors; D051176:beta Catenin / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; C493841:BCAR1 protein, human; D052117:Benzodioxoles; D050719:Crk-Associated Substrate Protein; D056741:Cyclin D; D016213:Cyclins; C514503:GSKIP protein, human; D016271:Proto-Oncogene Proteins c-myc; D011799:Quinazolines; D012097:Repressor Proteins; D051176:beta Catenin; C515233:saracatinib; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases