Department of Surgery, Tung's Taichung Metro Harbor Hospital, Taichung 435403, Taiwan.
Department of Life Sciences, National Chung Hsing University, Taichung 402204, Taiwan.
Biomolecules. 2021 Jun 9;11(6):860. doi: 10.3390/biom11060860.
Medullary thyroid cancer (MTC) is a neuroendocrine tumor that arises from the parafollicular C-cells, which produces the hormone calcitonin. RET is a transmembrane receptor protein-tyrosine kinase, which is highly expressed in MTC. Our previous studies reported that cyclin-dependent kinase 5 (CDK5) plays a crucial role in cancer progression, including MTC. However, the role of CDK5 in GDNF-induced RET signaling in medullary thyroid cancer proliferation remains unknown. Here, we investigated RET activation and its biochemically interaction with CDK5 in GDNF-induced medullary thyroid cancer proliferation. Our results demonstrated that GDNF stimulated RET phosphorylation and thus subsequently resulted in CDK5 activation by its phosphorylation. Activated CDK5 further caused STAT3 activation by its specific phosphorylation at Ser727. Moreover, we also found that GDNF treatment enhanced ERK1/2 and EGR1 activity, which is involved in p35 activation. Interestingly, we identified for the first time that CDK5 physically interacted with RET protein in MTC. Overall, our results provide a new mechanism for medullary thyroid cancer cell proliferation, suggesting that targeting CDK5 may be a promising therapeutic candidate for human medullary thyroid cancer in the near future.
甲状腺髓样癌（MTC）是一种起源于滤泡旁 C 细胞的神经内分泌肿瘤，该细胞产生降钙素。RET 是一种跨膜受体蛋白酪氨酸激酶，在 MTC 中高度表达。我们之前的研究报告称，细胞周期蛋白依赖性激酶 5（CDK5）在癌症进展中发挥着关键作用，包括 MTC。然而，CDK5 在 GDNF 诱导的 RET 信号通路促进甲状腺髓样癌细胞增殖中的作用尚不清楚。在这里，我们研究了 GDNF 诱导的甲状腺髓样癌细胞增殖过程中 RET 的激活及其与 CDK5 的生化相互作用。我们的结果表明，GDNF 刺激 RET 磷酸化，进而通过磷酸化激活 CDK5。激活的 CDK5 通过其在 Ser727 的特异性磷酸化进一步引起 STAT3 的激活。此外，我们还发现 GDNF 处理增强了 ERK1/2 和 EGR1 的活性，这涉及到 p35 的激活。有趣的是，我们首次发现 CDK5 与 MTC 中的 RET 蛋白发生物理相互作用。总的来说，我们的研究结果为甲状腺髓样癌细胞增殖提供了一种新的机制，提示靶向 CDK5 可能是未来治疗人类甲状腺髓样癌的一个有前途的候选药物。
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