Cdk5 regulates STAT3 activation and cell proliferation in medullary thyroid carcinoma cells
Cdk5 regulates STAT3 activation and cell proliferation in medullary thyroid carcinoma cells
复制标题
DOI：
10.1074/jbc.m607234200
复制
发表时间：
2007-02-02
影响因子：
4.8
通讯作者：
Lin, Shih-Yi
中科院分区：
文献类型：
--
作者：
Lin, Ho;Chen, Mei-Chih;Lin, Shih-Yi
甲状腺癌的生物学行为多种多样，病理机制尚不清楚。一些报告显示明显的淀粉样蛋白聚集伴甲状腺髓样癌（MTC）。神经变性中的淀粉样蛋白聚集导致Cdk5的过度激活和随后的神经元死亡。基于与淀粉样蛋白的联系，Cdk5在MTC中的作用值得研究。最初，我们在MTC细胞系中鉴定了Cdk5及其激活剂p35的表达。特异性抑制剂或短干扰RNA抑制Cdk5可降低MTC细胞系的增殖，揭示了Cdk5在MTC细胞生长中的重要性。尽管p35切割被认为是神经退行性变的重要因素，但似乎p35切割并不是Cdk5活性依赖性MTC细胞增殖的主要原因，因为抑制p35切割既不影响Cdk5活性，也不影响细胞生长。通过抗体中和清除淀粉样蛋白表明MTC细胞增殖是由降钙素来源的细胞外淀粉样蛋白和随后的Her2和Cdk5激活支持的。值得注意的是，STAT3通路通过Ser-727磷酸化参与了cdk5依赖性MTC细胞的增殖。此外，Cdk5抑制减少了MTC细胞中Cdk5-p35复合物和phospho-STAT3的核分布。最后，抑制Cdk5可以延缓体内肿瘤的形成，同时减少磷酸化stat3。我们的研究结果首次证明了Cdk5激酶在支持甲状腺髓样癌细胞增殖中的一种新的特异性作用，并可能为甲状腺癌的诊断和治疗开辟一个新的领域。
The biological behaviors of thyroid cancer are varied, and the pathological mechanisms remain unclear. Some reports indicated an apparent aggregation of amyloid accompanying medullary thyroid carcinoma (MTC). Amyloid aggregation in neurodegeneration leads to hyperactivation of Cdk5 and subsequent neuronal death. Based on the connection with amyloid, the role of Cdk5 in MTC is worthy of investigation. Initially, the expression of Cdk5 and its activator, p35, in MTC cell lines was identified. Cdk5 inhibition by specific inhibitors or short interfering RNA decreased the proliferation of MTC cell lines, which reveals the importance of Cdk5 in MTC cell growth. Although p35 cleavage has been considered as an important element in neurodegeneration, it seems that p35 cleavage was not a major cause in Cdk5 activity-dependent MTC cell proliferation because neither Cdk5 activity nor cell growth was affected by the inhibition of p35 cleavage. Clearance of amyloid by antibody neutralization indicated that MTC cell proliferation was supported by calcitonin-derived extracellular amyloid and subsequent Her2 and Cdk5 activation. Significantly, the STAT3 pathway was involved in Cdk5-dependent proliferation of MTC cells through Ser-727 phosphorylation. In addition, Cdk5 inhibition reduced nuclear distributions of both the Cdk5-p35 complex and phospho-STAT3 in MTC cells. Finally, Cdk5 inhibition retarded tumor formation in vivo accompanying the reduction of phospho-STAT3. Our findings suggest the first demonstration of a novel and specific role for Cdk5 kinase in supporting the proliferation of the medullary thyroid carcinoma cells and could shed light on a new field for diagnosis and therapy of thyroid cancer.