Targeting src family kinases inhibits growth and lymph node metastases of prostate cancer in an orthotopic nude mouse model
Targeting src family kinases inhibits growth and lymph node metastases of prostate cancer in an orthotopic nude mouse model
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DOI：
10.1158/0008-5472.can-07-2997
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发表时间：
2008-05-01
期刊：
影响因子：
11.2
通讯作者：
Gallick, Gary E.
中科院分区：
文献类型：
--
作者：
Park, Serk In;Zhang, Jing;Gallick, Gary E.
在人类肿瘤的进展期，常可观察到非受体蛋白酪氨酸激酶(SFK)家族成员的异常表达和/或活性。在前列腺癌中，两个SFK(Src和Lyn)被明确地与肿瘤的生长和进展有关。然而，在临床前模型中还没有数据表明Src抑制剂对前列腺癌生长和/或转移的潜在疗效。在这项研究中，我们使用小分子SFK/AB1激酶抑制剂达沙替尼，目前正在进行实体肿瘤的临床试验，以检测在体外和体内抑制前列腺肿瘤细胞中SFK的效果。在体外，达沙替尼抑制Src和Lyn的活性，导致细胞增殖、迁移和侵袭减少。在原位裸鼠模型中，达沙替尼治疗有效地抑制了活化的SFK的表达，从而抑制了雄激素敏感和雄激素耐药肿瘤的生长和淋巴结转移。在原发肿瘤中，抑制SFK导致细胞增殖减少(通过增殖细胞核抗原的免疫组织化学确定)。在……里面。在体外，小干扰RNA(SiRNA)介导的对Lyn的抑制影响细胞增殖；siRNA对Src的抑制主要影响细胞的迁移。因此，我们得出结论，SFK是治疗前列腺癌的有前景的治疗靶点，并且Src和Lyn的活性影响前列腺癌生长和进展所需的不同细胞功能。
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/ Ab1 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.