Spleen Tyrosine Kinase Functions as a Tumor Suppressor in Melanoma Cells by Inducing Senescence-like Growth Arrest
Spleen Tyrosine Kinase Functions as a Tumor Suppressor in Melanoma Cells by Inducing Senescence-like Growth Arrest
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DOI：
10.1158/0008-5472.can-08-2690
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发表时间：
2009-04-01
期刊：
影响因子：
11.2
通讯作者：
Tartare-Deckert, Sophie
中科院分区：
文献类型：
--
作者：
Bailet, Olivier;Fenouille, Nina;Tartare-Deckert, Sophie
控制细胞衰老的肿瘤抑制通路的缺失是恶性转化的关键步骤。脾酪氨酸激酶(Syk)是一种细胞质酪氨酸激酶，最近被认为与黑色素瘤的肿瘤抑制有关，黑色素瘤是一种致命的皮肤癌，源于产生色素的黑素细胞。然而，Syk抑制黑色素瘤生长的机制尚不清楚。在这里，我们报告了Syk在黑色素瘤细胞中的重新表达诱导了细胞周期蛋白依赖性激酶(CDK)抑制物p21的P53依赖的表达。还有一个衰老计划。我们首先观察到Syk在黑色素瘤细胞亚群中的表达缺失，主要是通过DNA甲基化介导的基因沉默，并在去甲基化药物5-氮杂-2-脱氧胞苷处理后恢复。我们分析了Syk表观遗传失活的意义，发现Syk在黑色素瘤细胞中的重新导入显著降低了克隆形成的存活率和三维肿瘤球体的生长和侵袭。值得注意的是，重新表达Syk的黑色素瘤细胞表现出衰老细胞的特征，包括增殖活性和DNA合成减少，形态大而扁平，衰老相关的β-半乳糖苷酶活性，以及异染色灶。这种表型伴随着低磷酸化的视网膜母细胞瘤蛋白(Rb)和p21的积聚，这依赖于功能性的P53。我们的结果强调了Syk酪氨酸激酶在调节细胞衰老中的新作用，并确认Syk介导的衰老是一种新的肿瘤抑制途径，其失活可能与黑色素瘤的发生有关。[癌症资源2009；69(7)：2748-56]
Loss of tumor-suppressive pathways that control cellular senescence is a crucial step in malignant transformation. Spleen tyrosine kinase (Syk) is a cytoplasmic tyrosine kinase that has been recently implicated in tumor suppression of melanoma, a deadly skin cancer derived from pigment-producing melanocytes. However, the mechanism by which Syk suppresses melanoma growth remains unclear. Here, we report that reexpression of Syk in melanoma cells induces a p53-dependent expression of the cyclin-dependent kinase (cdk) inhibitor p21. and a senescence program. We first observed that Syk expression is lost in a subset of melanoma cell lines, primarily by DNA methylation-mediated gene silencing and restored after treatment with the demethylating agent 5-aza-2-deoxycytidine. We analyzed the significance of epigenetic inactivation of Syk and found that reintroduction of Syk in melanoma cells dramatically reduces clonogenic survival and three-dimensional tumor spheroid growth and invasion. Remarkably, melanoma cells reexpressing Syk display hallmarks of senescent cells, including reduction of proliferative activity and DNA synthesis, large and flattened morphology, senescence-associated beta-galactosidase activity, and heterochromatic foci. This phenotype is accompanied by hypophosphorylated retinoblastoma protein (Rb) and accumulation of p21, which depends on functional p53. Our results highlight a new role for Syk tyrosine kinase in regulating cellular senescence and identify Syk-mediated senescence as a novel tumor suppressor pathway the inactivation of which may contribute to melanoma tumorigenicity. [Cancer Res 2009;69(7):2748-56]