Laboratori d'Oncologia Molecular, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Gran Via de L'Hospitalet 199, L'Hospitalet, Barcelona 08907, Spain.
Cell Death Differ. 2010 Aug;17(8):1335-44. doi: 10.1038/cdd.2010.21. Epub 2010 Mar 5.
Apoptosis induced by most stimuli proceeds through the mitochondrial pathway. One such stimulus is nutrient deprivation. In this study we studied death induced by glucose deprivation in cells deficient in Bax and Bak. These cells cannot undergo mitochondrial outer membrane permeabilization (MOMP) during apoptosis, but they undergo necrosis when treated with MOMP-dependent apoptotic stimuli. We find in these cells that glucose deprivation, rather than inducing necrosis, triggered apoptosis. Cell death required caspase activation as inhibition of caspases with peptidic inhibitors prevented death. Glucose deprivation-induced death displayed many hallmarks of apoptosis, such as caspase cleavage and activity, phosphatidyl-serine exposure and cleavage of caspase substrates. Neither overexpression of Bcl-xL nor knockdown of caspase-9 prevented death. However, transient or stable knockdown of caspase-8 or overexpression of CrmA inhibited apoptosis. Cell death was not inhibited by preventing death receptor-ligand interactions, by overexpression of c-FLIP or by knockdown of RIPK1. Glucose deprivation induced apoptosis in the human tumor cell line HeLa, which was prevented by knockdown of caspase-8. Thus, we have found that glucose deprivation can induce a death receptor-independent, caspase-8-driven apoptosis, which is engaged to kill cells that cannot undergo MOMP.
大多数刺激诱导的细胞凋亡都通过线粒体途径进行。其中一种刺激是营养物质的剥夺。在这项研究中，我们研究了 Bax 和 Bak 缺陷细胞中葡萄糖剥夺诱导的死亡。这些细胞在接受依赖线粒体膜通透性改变（MOMP）的凋亡刺激时不能发生线粒体外膜通透性改变（MOMP），但会发生坏死。我们在这些细胞中发现，葡萄糖剥夺不是诱导坏死，而是触发了凋亡。细胞死亡需要半胱天冬酶的激活，因为用肽抑制剂抑制半胱天冬酶可以防止死亡。葡萄糖剥夺诱导的死亡显示出许多凋亡的特征，如半胱天冬酶的切割和活性、磷脂酰丝氨酸的暴露以及半胱天冬酶底物的切割。Bcl-xL 的过表达或 caspase-9 的敲低都不能阻止死亡。然而，瞬时或稳定敲低 caspase-8 或过表达 CrmA 抑制了凋亡。阻止死亡受体配体相互作用、过表达 c-FLIP 或敲低 RIPK1 并不能抑制细胞死亡。葡萄糖剥夺可诱导人肿瘤细胞系 HeLa 发生细胞凋亡，而 caspase-8 的敲低可阻止该凋亡的发生。因此，我们发现葡萄糖剥夺可以诱导一种不依赖于死亡受体、由 caspase-8 驱动的凋亡，这种凋亡可以杀死不能发生 MOMP 的细胞。
