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PMID: 18679417 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

Src family kinase oncogenic potential and pathways in prostate cancer as revealed by AZD0530.

Oncogene ·Vol. 27 ·No. 49 ·2008-10-23 ·Pages 6365-75

Chang YM, Bai L, Liu S, Yang JC, Kung HJ, Evans CP

Abstract

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.

MeSH Terms
Antineoplastic Agents/chemistry,pharmacology Benzodioxoles/chemistry,pharmacology Cell Cycle/drug effects Cell Line, Tumor Cell Movement/drug effects Cell Proliferation/drug effects Crk-Associated Substrate Protein/metabolism Cyclin D Cyclins/metabolism Dose-Response Relationship, Drug Enzyme Activation/drug effects Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors Focal Adhesion Protein-Tyrosine Kinases/metabolism Gene Expression Regulation, Neoplastic/drug effects Humans Inhibitory Concentration 50 Male Molecular Structure Phosphorylation/drug effects Prostatic Neoplasms/drug therapy,genetics,pathology Proto-Oncogene Proteins c-akt/metabolism Proto-Oncogene Proteins c-myc/metabolism Quinazolines/chemistry,pharmacology Repressor Proteins/metabolism Time Factors beta Catenin/metabolism src-Family Kinases/antagonists & inhibitors,genetics,metabolism
Chemicals
Antineoplastic Agents BCAR1 protein, human Benzodioxoles Crk-Associated Substrate Protein Cyclin D Cyclins GSKIP protein, human Proto-Oncogene Proteins c-myc Quinazolines Repressor Proteins beta Catenin saracatinib Focal Adhesion Protein-Tyrosine Kinases src-Family Kinases Proto-Oncogene Proteins c-akt Extracellular Signal-Regulated MAP Kinases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Chang Y-M
Department of Urology, University of California at Davis, Sacramento, CA 95817, USA.
Bai L
Liu S
Yang J C
Kung H-J
Evans C P
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Article Info
Journal
Oncogene
Abbr.
Oncogene
ISSN
1476-5594
DOI
10.1038/onc.2008.250
Published
2008-10-23
Epub
2008-00-04
Pages
6365-75
Language
English
Region
England
NLM ID
8711562
PMCID
PMC4294546
Subset
IM
Grants
NCI NIH HHS · R01 CA114575-01 · United States
NIDDK NIH HHS · R01 DK052659-07 · United States
NIDDK NIH HHS · R01 DK52659 · United States
NIDDK NIH HHS · R01 DK052659 · United States
NIDDK NIH HHS · R01 DK052659-08 · United States
NIDDK NIH HHS · R01 DK052659-06 · United States
NIDDK NIH HHS · R01 DK078243-01 · United States
NCI NIH HHS · R01 CA114575-02 · United States
NIDDK NIH HHS · K08 DK60748-01 · United States
NIDDK NIH HHS · K08 DK060748 · United States
NIDDK NIH HHS · R01 DK052659-09 · United States
NIDDK NIH HHS · R01 DK078243 · United States
NCI NIH HHS · R01 CA114575 · United States
External Links
PubMed source DOI: 10.1038/onc.2008.250 PMC Full Text View journal details
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