Targeting SRC family kinases inhibits growth and lymph node metastases of prostate cancer in an orthotopic nude mouse model.
Aberrant expression and/or activity of members of the Src family of nonreceptor protein tyrosine kinases (SFK) are commonly observed in progressive stages of human tumors. In prostate cancer, two SFKs (Src and Lyn) have been specifically implicated in tumor growth and progression. However, there are no data in preclinical models demonstrating potential efficacy of Src inhibitors against prostate cancer growth and/or metastasis. In this study, we used the small molecule SFK/Abl kinase inhibitor dasatinib, currently in clinical trials for solid tumors, to examine in vitro and in vivo effects of inhibiting SFKs in prostate tumor cells. In vitro, dasatinib inhibits both Src and Lyn activity, resulting in decreased cellular proliferation, migration, and invasion. In orthotopic nude mouse models, dasatinib treatment effectively inhibits expression of activated SFKs, resulting in inhibition of both tumor growth and development of lymph node metastases in both androgen-sensitive and androgen-resistant tumors. In primary tumors, SFK inhibition leads to decreased cellular proliferation (determined by immunohistochemistry for proliferating cell nuclear antigen). In vitro, small interfering RNA (siRNA)-mediated inhibition of Lyn affects cellular proliferation; siRNA inhibition of Src affects primarily cellular migration. Therefore, we conclude that SFKs are promising therapeutic targets for treatment of human prostate cancer and that Src and Lyn activities affect different cellular functions required for prostate tumor growth and progression.
Park
Serk In
SI
The Program in Cancer Biology, Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, TX 77030, USA.
Zhang
Jing
J
Phillips
Kacy A
KA
Araujo
John C
JC
Najjar
Amer M
AM
Volgin
Andrei Y
AY
Gelovani
Juri G
JG
Kim
Sun-Jin
SJ
Wang
Zhengxin
Z
Gallick
Gary E
GE
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D000069439:Dasatinib; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D011743:Pyrimidines / Q000627:therapeutic use*; D013844:Thiazoles / Q000627:therapeutic use*; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D050719:Crk-Associated Substrate Protein; D011743:Pyrimidines; D013844:Thiazoles; D014443:Tyrosine; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D000069439:Dasatinib