衰老
生物
谷氨酰胺
细胞生长
癌症研究
安普克
癌变
细胞生物学
自噬
激酶
蛋白激酶A
癌症
生物化学
遗传学
细胞凋亡
氨基酸
作者
Lei Chen,Wenjing Zhang,Dan Chen,Quan Yang,Shutao Sun,Zhenwei Dai,Zhengzheng Li,Xuemei Liang,Chaoqun Chen,Yuexia Jiao,Lili Zhi,Lianmei Zhao,Jinrui Zhang,Xuefeng Li,Jie Zhao,Man Li,Yang Wang,Yangfan Qi
标识
DOI:10.1038/s41392-023-01367-x
摘要
Cellular senescence provides a protective barrier against tumorigenesis in precancerous or normal tissues upon distinct stressors. However, the detailed mechanisms by which tumor cells evade premature senescence to malignant progression remain largely elusive. Here we reported that RBM4 adversely impacted cellular senescence to favor glutamine-dependent survival of esophageal squamous cell carcinoma (ESCC) cells by dictating the activity of LKB1, a critical governor of cancer metabolism. The level of RBM4 was specifically elevated in ESCC compared to normal tissues, and RBM4 overexpression promoted the malignant phenotype. RBM4 contributed to overcome H-RAS- or doxorubicin-induced senescence, while its depletion caused P27-dependent senescence and proliferation arrest by activating LKB1-AMPK-mTOR cascade. Mechanistically, RBM4 competitively bound LKB1 to disrupt the LKB1/STRAD/MO25 heterotrimeric complex, subsequently recruiting the E3 ligase TRIM26 to LKB1, promoting LKB1 ubiquitination and degradation in nucleus. Therefore, such molecular process leads to bypassing senescence and sustaining cell proliferation through the activation of glutamine metabolism. Clinically, the ESCC patients with high RBM4 and low LKB1 have significantly worse overall survival than those with low RBM4 and high LKB1. The RBM4 high/LKB1 low expression confers increased sensitivity of ESCC cells to glutaminase inhibitor CB-839, providing a novel insight into mechanisms underlying the glutamine-dependency to improve the efficacy of glutamine inhibitors in ESCC therapeutics.
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