靶向转移性黑色素瘤中的细胞周期蛋白依赖性激酶 5。
Targeting the cyclin-dependent kinase 5 in metastatic melanoma.
机构信息
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215.
Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115.
出版信息
Proc Natl Acad Sci U S A. 2020 Apr 7;117(14):8001-8012. doi: 10.1073/pnas.1912617117. Epub 2020 Mar 19.
Abstract
The cyclin-dependent kinase 5 (CDK5), originally described as a neuronal-specific kinase, is also frequently activated in human cancers. Using conditional CDK5 knockout mice and a mouse model of highly metastatic melanoma, we found that CDK5 is dispensable for the growth of primary tumors. However, we observed that ablation of CDK5 completely abrogated the metastasis, revealing that CDK5 is essential for the metastatic spread. In mouse and human melanoma cells CDK5 promotes cell invasiveness by directly phosphorylating an intermediate filament protein, vimentin, thereby inhibiting assembly of vimentin filaments. Chemical inhibition of CDK5 blocks the metastatic spread of patient-derived melanomas in patient-derived xenograft (PDX) mouse models. Hence, inhibition of CDK5 might represent a very potent therapeutic strategy to impede the metastatic dissemination of malignant cells.
摘要
周期蛋白依赖性激酶 5（CDK5）最初被描述为一种神经元特异性激酶，也经常在人类癌症中被激活。使用条件性 CDK5 敲除小鼠和高转移性黑色素瘤的小鼠模型，我们发现 CDK5对于原发性肿瘤的生长不是必需的。然而，我们观察到 CDK5 的缺失完全阻断了转移，表明 CDK5 对于转移扩散是必需的。在小鼠和人黑色素瘤细胞中，CDK5 通过直接磷酸化中间丝蛋白波形蛋白来促进细胞侵袭，从而抑制波形蛋白丝的组装。CDK5 的化学抑制可阻断患者来源的异种移植（PDX）小鼠模型中黑色素瘤的转移扩散。因此，抑制 CDK5 可能代表一种非常有效的治疗策略，以阻止恶性细胞的转移扩散。
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