Non-apoptotic cell death induced by opening the large conductance mechanosensitive channel MscL in hepatocellular carcinoma HepG2 cells
Non-apoptotic cell death induced by opening the large conductance mechanosensitive channel MscL in hepatocellular carcinoma HepG2 cells
复制标题
打开大电导机械敏感通道MscL诱导肝癌HepG2细胞非凋亡细胞死亡
DOI：
10.1016/j.biomaterials.2020.120061
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发表时间：
2020
期刊：
影响因子：
14
通讯作者：
Li Yuezhou
中科院分区：
文献类型：
--
作者：
Wen Xiaoxu;Tang Siyang;Hong Feifan;Wang Xiaomin;Chen Sihan;Hong Lang;Ye Jia;Li Xia;Shang Shiqiang;Jiang Mizu;Mao Jianhua;Shu Qiang;Li Yuezhou
大多数抗癌疗法通过触发细胞凋亡来消除恶性细胞。然而，由于基因突变或异质性，大多数恶性癌细胞对凋亡具有抗性。在这里，我们报告了打开细菌大电导机械敏感通道（MscL）的孔提供了一种诱导非凋亡细胞死亡的新方法。功能获得型突变体V23A-MscL和化学反应型突变体G26C-MscL可以在肝癌HepG2细胞中功能性表达。V23A-MscL自发打开，G26C-MscL也响应其化学激活剂MTSET。打开MscL通道导致细胞内Ca2+浓度增加，抑制细胞生长和活力。在小鼠模型中，mtset激活的G26C通道诱导坏死，而V23A-MscL表达导致HepG2细胞胞质空泡化细胞死亡并抑制肿瘤生长。我们提出MscL可能作为一个纳米阀，通过它破坏细胞内稳态并导致恶性肿瘤细胞损伤，从而导致癌症治疗的新策略。
Most anticancer therapies trigger apoptosis to eliminate malignant cells. However, the majority of malignant cancer cells are resistant to apoptosis due to genetic mutations or heterogeneity. Here, we report that opening the pore of the bacterial large conductance mechanosensitivity channel (MscL) provides a novel approach of inducing non-apoptotic cell death. The gain-of-function mutant V23A-MscL and chemically responsive mutant G26C-MscL can be functionally expressed in hepatocellular carcinoma HepG2 cells. V23A-MscL spontaneously opens, and G26C-MscL also responds to its chemical activator MTSET. Opening of the MscL channel causes increased intracellular Ca2+concentration and suppressed cell growth and viability. MTSET-activated G26C channels induce necrosis, while V23A-MscL expression leads to cytoplasmic vacuolization cell death in HepG2 cells and suppresses tumor growth in a mouse model. We propose that MscL may act as a nanovalve through which intracellular homeostasis suffers a disruption and results in malignant tumor cell damage, leading to a new strategy for cancer therapy.