National Translational Science Center for Molecular Medicine, Xi'an, 710032, China.
Department of Cell Biology, School of Basic Medicine, The Fourth Military Medical University, Xi'an, 710032, China.
Apoptosis. 2019 Aug;24(7-8):673-685. doi: 10.1007/s10495-019-01550-y.
Chemotherapeutic resistance always results in poor clinical outcomes of cancer patients and its intricate mechanisms are large obstacles in overcoming drug resistance. CCR4-NOT transcription complex subunit 3 (CNOT3), a post-translational regulator, is suggested to be involved in cancer development and progression. However, its role in chemotherapeutic resistance is not well understood. In this study, after screening the CNOT3 mRNA in a cancer microarray database called Oncomine and examining the expression levels of CNOT3 mRNA in normal tissues and lung cancer tissues, we found that CNOT3 was up-regulated in lung cancer tissues. Besides, its high-expression was associated with poor prognosis of lung cancer patients. We also found higher expression level of CNOT3 and lower expression level of receptor-interacting protein kinase 3 (RIPK3) in cisplatin-resistant A549 (A549/DDP) cells, and knocking down CNOT3 expression could sensitize A549/DDP cells to cisplatin-induced apoptosis. We demonstrated that CNOT3 depletion up-regulated the expression level of RIPK3 and the enhanced apoptosis was mediated by the elevated RIPK3 to further trigger Caspase 8 activation. Taken together, our results reveal a role of CNOT3 in cisplatin resistance of lung cancer and provide a potential target for lung cancer therapy.
化疗耐药性总是导致癌症患者临床预后不良，其复杂的机制是克服耐药性的巨大障碍。CCR4-NOT 转录复合物亚基 3（CNOT3）是一种翻译后调节因子，被认为参与癌症的发生和发展。然而，其在化疗耐药性中的作用尚不清楚。在本研究中，我们在癌症微阵列数据库 Oncomine 中筛选 CNOT3 mRNA，并检测正常组织和肺癌组织中 CNOT3 mRNA 的表达水平，发现 CNOT3 在肺癌组织中上调。此外，其高表达与肺癌患者的不良预后相关。我们还发现，在顺铂耐药的 A549（A549/DDP）细胞中，CNOT3 的表达水平较高，而受体相互作用蛋白激酶 3（RIPK3）的表达水平较低，敲低 CNOT3 表达可使 A549/DDP 细胞对顺铂诱导的凋亡敏感。我们证明，CNOT3 耗竭上调了 RIPK3 的表达水平，增强的凋亡是通过升高的 RIPK3 进一步触发 Caspase 8 激活来介导的。总之，我们的结果揭示了 CNOT3 在肺癌顺铂耐药中的作用，并为肺癌治疗提供了一个潜在的靶点。
