SKI-606, an Src inhibitor, reduces tumor growth, invasion, and distant metastasis in a mouse model of thyroid cancer.
SKI-606, an Src inhibitor, reduces tumor growth, invasion, and distant metastasis in a mouse model of thyroid cancer.
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DOI：
10.1158/1078-0432.ccr-11-2892
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发表时间：
2012-03-01
期刊：
影响因子：
--
通讯作者：
Cheng SY
中科院分区：
文献类型：
--
作者：
Kim WG;Guigon CJ;Fozzatti L;Park JW;Lu C;Willingham MC;Cheng SY
Src在包括甲状腺癌在内的多种人类癌症中过度表达或过度激活。Src是多种信号通路的中心介体，在肿瘤发生和癌症进展中起重要作用。在这项研究中，我们评估了Src抑制剂SKI-606（博舒替尼）在具有组成性激活Src的自发性转移性甲状腺癌模型（ThrbPV/PVPten+/−小鼠）中的作用。ThrbPV/PVPten+/−小鼠用SKI-606或溶剂对照处理，从6周龄开始，直到小鼠死于甲状腺癌。我们评估了SKI-606对甲状腺癌进展的影响，并分析了SKI-606对异常Src介导的信号传导的影响。SKI-606有效抑制Src及其下游靶点的异常激活，从而显著抑制甲状腺肿瘤的生长，从而延长治疗小鼠的生存期。虽然Src抑制不诱导细胞凋亡，但它通过影响细胞周期进程的关键调节因子的表达来降低细胞增殖。重要的是，SKI-606显著防止甲状腺癌细胞的去分化、血管侵袭和肺转移。这些反应是通过下调丝裂原活化蛋白激酶途径和抑制上皮-间充质转化来调节的。我们的研究结果表明，Src在甲状腺癌的进展中至关重要，使口服SKI-606成为难治性甲状腺癌的一种有前途的治疗策略。
Src is over-expressed or hyper-activated in a variety of human cancers including thyroid carcinoma. Src is a central mediator in multiple signaling pathways that are important in oncogenesis and cancer progression. In this study, we evaluated the effects of a Src inhibitor, SKI-606 (bosutinib), in a spontaneous metastatic thyroid cancer model with constitutively activated Src (ThrbPV/PVPten+/− mice). ThrbPV/PVPten+/− mice were treated with SKI-606 or vehicle controls, beginning at 6 weeks of age until the mice succumbed to thyroid cancer. We assessed the effects of SKI-606 on thyroid cancer progression and analyzed the impact of SKI-606 on aberrant Src-mediated signaling. SKI-606 effectively inhibited aberrant activation of Src and its downstream targets to markedly inhibit the growth of thyroid tumor, thereby prolonging the survival of treated mice. While Src inhibition did not induce cell apoptosis, it decreased cell proliferation by affecting the expression of key regulators of cell cycle progression. Importantly, SKI-606 dramatically prevented de-differentiation, vascular invasion, and lung metastasis of thyroid cancer cells. These responses were meditated by down-regulation of mitogen-activated protein kinase pathways and inhibition of the epithelial-mesenchymal transition. Our findings suggest that Src is critical in the progression of thyroid cancer, making oral SKI-606 a promising treatment strategy for refractory thyroid cancer.