Proton pump inhibition induces autophagy as a survival mechanism following oxidative stress in human melanoma cells.
Proton pump inhibition induces autophagy as a survival mechanism following oxidative stress in human melanoma cells.
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质子泵的抑制可诱导自噬作为人类黑色素瘤细胞氧化应激后的生存机制。
DOI：
10.1038/cddis.2010.67
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发表时间：
2010-10-21
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
质子泵抑制剂（PPI）以肿瘤酸性pH为靶点，在黑色素瘤中具有抗肿瘤作用。质子泵抑制剂埃索美拉唑（ESOM）通过一种半胱天冬酶依赖性途径杀死黑色素瘤细胞，该途径涉及胞质酸化和肿瘤pH的碱化。在本文中，我们进一步研究了埃索美拉唑诱导黑色素瘤细胞死亡的机制。埃索美拉唑通过线粒体功能障碍和NADPH氧化酶的参与迅速诱导活性氧物质（ROS）的积累。ROS清除剂N - 乙酰半胱氨酸（NAC）以及对NADPH氧化酶的抑制显著降低了埃索美拉唑诱导的细胞死亡，这与胞质酸化的抑制作用一致。自噬是一种导致溶酶体降解以及蛋白质和细胞器循环利用的细胞分解代谢途径，是癌细胞在代谢应激下的一种防御机制。埃索美拉唑诱导自噬体的早期积累，同时降低自噬通量，这通过对LC3 - II积累的蛋白质印迹（WB）分析以及荧光显微镜观察到。此外，埃索美拉唑治疗降低了哺乳动物雷帕霉素靶蛋白信号通路，表现为观察到p70 - S6K和4 - EBP1磷酸化降低。通过敲低Atg5和Beclin - 1的表达来抑制自噬显著增加了埃索美拉唑的细胞毒性，这表明自噬在埃索美拉唑处理的细胞中具有保护作用。所呈现的数据表明，自噬是一种适应性生存机制，可克服药物诱导的细胞应激和细胞毒性，包括由质子泵抑制介导的pH稳态改变。
Proton pump inhibitors (PPI) target tumour acidic pH and have an antineoplastic effect in melanoma. The PPI esomeprazole (ESOM) kills melanoma cells through a caspase-dependent pathway involving cytosolic acidification and alkalinization of tumour pH. In this paper, we further investigated the mechanisms of ESOM-induced cell death in melanoma. ESOM rapidly induced accumulation of reactive oxygen species (ROS) through mitochondrial dysfunctions and involvement of NADPH oxidase. The ROS scavenger N-acetyl--cysteine (NAC) and inhibition of NADPH oxidase significantly reduced ESOM-induced cell death, consistent with inhibition of cytosolic acidification. Autophagy, a cellular catabolic pathway leading to lysosomal degradation and recycling of proteins and organelles, represents a defence mechanism in cancer cells under metabolic stress. ESOM induced the early accumulation of autophagosomes, at the same time reducing the autophagic flux, as observed by WB analysis of LC3-II accumulation and by fluorescence microscopy. Moreover, ESOM treatment decreased mammalian target of rapamycin signalling, as reduced phosphorylation of p70-S6K and 4-EBP1 was observed. Inhibition of autophagy by knockdown of Atg5 and Beclin-1 expression significantly increased ESOM cytotoxicity, suggesting a protective role for autophagy in ESOM-treated cells. The data presented suggest that autophagy represents an adaptive survival mechanism to overcome drug-induced cellular stress and cytotoxicity, including alteration of pH homeostasis mediated by proton pump inhibition.
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影响因子：
13.3
作者：
Ostenfeld, Marie Stampe;Hoyer-Hansen, Maria;Jaattela, Maria
通讯作者：
Jaattela, Maria
影响因子：
10.3
作者：
Luciani, F;Spada, M;Fais, S
通讯作者：
Fais, S
影响因子：
2.9
作者：
NEGENDANK, W
通讯作者：
NEGENDANK, W
影响因子：
5.8
作者：
Martínez-Zaguilán, R;Raghunand, N;Gillies, RJ
通讯作者：
Gillies, RJ
影响因子：
4
作者：
González-Polo, RA;Boya, P;Kroemer, G
通讯作者：
Kroemer, G