CEMIP promotes small cell lung cancer proliferation by activation of glutamine metabolism via FBXW7/c-Myc-dependent axis
CEMIP promotes small cell lung cancer proliferation by activation of glutamine metabolism via FBXW7/c-Myc-dependent axis
复制标题
CEMIP 通过 FBXW7/c-Myc 依赖性轴激活谷氨酰胺代谢促进小细胞肺癌增殖
DOI：
10.1016/j.bcp.2023.115446
复制
发表时间：
--
期刊：
影响因子：
--
通讯作者：
Jie Yang
中科院分区：
文献类型：
--
作者：
Xiaoxiang Mo;Xiaoju Shen;Xiaocheng Mo;Fei Yu;Weidan Tan;Zhihua Deng;Jingchuan He;Zhuo Luo;Zhiquan Chen;Jie Yang
小细胞肺癌（small cell lung cancer，SCLC）是恶性程度最高的肺癌，具有生长迅速、早期转移等特点，但目前仍缺乏有效的靶向治疗以改善预后。在这里，我们证明了一种新的致癌蛋白，细胞迁移诱导透明质酸结合蛋白（CEMIP），在SCLC组织中比在非癌组织中强烈过表达，并且CEMIP的高表达预测了临床标本和公共数据库（GEPIA 2和CPTAC）中大样本量队列的不良结局。液相色谱质谱（LC-MS）和体外/体内功能测定表明，CEMIP通过增加SCLC细胞中谷氨酰胺消耗及其代谢产物（谷氨酸和谷胱甘肽）水平而促进增殖。此外，添加GLS 1抑制剂CB-839显著降低了CEMIP诱导的SCLC细胞增殖。从机制上讲，除了作为支架蛋白外，CEMIP还通过抑制c-Myc泛素化和通过阻碍FBXW 7（E3泛素连接酶）与其靶底物c-Myc之间的相互作用增加c-Myc稳定性和核积累来促进谷氨酰胺依赖性细胞增殖。总之，我们的研究结果揭示了CEMIP通过FBXW 7/c-Myc依赖性轴在维持SCLC生长中的新致癌作用，并提供了新的证据，即抑制CEMIP可能是治疗SCLC的潜在治疗策略。
Small cell lung cancer (SCLC) is the most malignant lung cancer with rapid growth and early metastasis, but still lacks effective targeted therapies to improve the prognosis. Here, we demonstrated that a novel oncogenic protein, cell migration inducing hyaluronic binding protein (CEMIP), was robustly overexpressed in SCLC tissues than that in noncancerous tissues and high expression of CEMIP predicted poor outcomes in clinical specimens and in large sample size cohorts from public databases (GEPIA 2 and CPTAC). Liquid chromatography mass spectrometry (LC-MS) and in vitro/in vivo functional assays indicated that CEMIP contributed to the proliferation by increasing glutamine consumption and their metabolites (glutamate and glutathione) levels in SCLC cells. Moreover, the addition of a GLS1 inhibitor CB-839 dramatically reduced CEMIP-induced SCLC cell proliferation. Mechanistically, beyond as a scaffold protein, CEMIP facilitates glutamine-dependent cell proliferation through inhibiting c-Myc ubiquitination and increasing c-Myc stabilization and nuclear accumulation via hindering the interaction between FBXW7 (a E3 ubiquitin ligase) and its target substrate c-Myc. Taken together, our findings reveal a novel oncogenic role of CEMIP in sustaining SCLC growth via FBXW7/c-Myc-dependent axis, and provide new evidence that inhibition of CEMIP might be a potential therapeutic strategy for the treatment of SCLC.