TIM-4 orchestrates mitochondrial homeostasis to promote lung cancer progression via ANXA2/PI3K/AKT/OPA1 axis.
TIM-4 orchestrates mitochondrial homeostasis to promote lung cancer progression via ANXA2/PI3K/AKT/OPA1 axis.
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DOI：
10.1038/s41419-023-05678-3
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发表时间：
2023-02-20
影响因子：
9
通讯作者：
Gao, Lifen
中科院分区：
文献类型：
--
作者：
Wang, Yuzhen;Wang, Yingchun;Liu, Wen;Ding, Lu;Zhang, Xiaodi;Wang, Bo;Tong, Zheng;Yue, Xuetian;Li, Chunyang;Xu, Liyun;Wu, Zhuanchang;Liang, Xiaohong;Ma, Chunhong;Gao, Lifen
线粒体功能和稳态对肺癌细胞的增殖至关重要。含T细胞免疫球蛋白和粘蛋白结构域的分子4（TIM-4）促进肺癌的发生和发展。然而，TIM-4在肿瘤细胞线粒体稳态中的作用仍然完全未知。在本研究中，我们发现TIM-4通过氧化磷酸化（OXPHOS）途径促进肺癌细胞的生长和增殖。因此，抑制OXPHOS逆转了TIM-4诱导的肺癌细胞增殖。值得注意的是，TIM-4通过增强L-OPA 1蛋白表达促进线粒体融合。TIM-4通过PI 3 K/AKT信号通路调节L-OPA 1蛋白表达，并与ANXA 2相互作用，促进PI 3 K/AKT信号通路的激活。总之，TIM-4通过ANXA 2/PI 3 K/AKT/OPA 1轴促进肺癌细胞的氧化磷酸化以加速肿瘤进展，这为TIM-4在调节肿瘤细胞代谢中的潜在作用提供了重要的新线索。
Mitochondrial function and homeostasis are critical to the proliferation of lung cancer cells. T-cell immunoglobulin and mucin domain-containing molecule 4 (TIM-4) promotes the development and progression of lung cancer. However, the role of TIM-4 in mitochondria homeostasis in tumor cells remains completely unknown. In this study, we found that TIM-4 promoted growth and proliferation of lung cancer cells by the oxidative phosphorylation (OXPHOS) pathway. Consistently, inhibition of OXPHOS reversed TIM-4-induced proliferation of lung cancer cells. Notably, TIM-4 promoted mitochondrial fusion via enhancing L-OPA1 protein expression. Mechanistically, TIM-4 regulated protein of L-OPA1 through the PI3K/AKT pathway, and TIM-4 interacted with ANXA2 to promote the activation of PI3K/AKT signaling. Collectively, TIM-4 promotes oxidative phosphorylation of lung cancer cells to accelerate tumor progress via ANXA2/PI3K/AKT/OPA1 axis, which sheds significant new lights on the potential role of TIM-4 in regulating tumor cell metabolism.
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