Deficiency in apoptotic effectors bax and bak reveals an autophagic cell death pathway initiated by photodamage to the endoplasmic reticulum
Deficiency in apoptotic effectors bax and bak reveals an autophagic cell death pathway initiated by photodamage to the endoplasmic reticulum
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DOI：
10.4161/auto.2730
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发表时间：
2006-07-01
期刊：
影响因子：
13.3
通讯作者：
Agostinis, P.
中科院分区：
文献类型：
--
作者：
Buytaert, E.;Callewaert, G.;Agostinis, P.
有效利用细胞死亡机制用于治疗目的需要鉴定使癌细胞死亡的分子事件以及响应抗癌治疗而激活的促死亡和促存活机制的细胞内元件。光动力疗法（PDT）是利用活性氧的产生来杀死癌细胞的抗癌疗法的范例。在这项研究中，我们已经确定了光损伤的sarco（endo）浆网Cat（2+）-ATP酶（SERCA）泵和随之而来的损失ER-Ca 2+稳态的最顶端的分子事件导致细胞死亡金丝桃素光敏细胞。在ER-Ca 2+排空的下游，激活半胱天冬酶依赖性和非依赖性途径以确保细胞死亡。作为细胞死亡方式的凋亡诱导依赖于促凋亡Box和巴克蛋白的可用性，它们是线粒体外膜透化（MOMP）和随后的半胱天冬酶激活的重要效应物。在Bax（-/-）/巴克（-/-）细胞中，依赖于持续自噬的非凋亡途径使氧化损伤的细胞死亡。这些结果表明，在这种氧化应激的范例中死亡的决定是采取上游的β-依赖性MOMP，并且金丝桃素-PDT诱导的对ER的不可逆的光损伤作为自噬性细胞死亡途径的触发剂在凋亡缺陷细胞中起作用。
Efficient exploitation of cell death mechanisms for therapeutic purpose requires the identification of the molecular events committing cancer cells to death and the intracellular elements of the pro-death and pro-survival machinery activated in response to the anticancer therapy. Photodynamic therapy (PDT) is a paradigm of anticancer therapy utilizing the generation of reactive oxygen species to kill the cancer cells. In this study we have identified the photodamage to the sarco(endo)plasmic-reticulum Cat(2+)-ATPase (SERCA) pump and consequent loss in the ER-Ca2+ homeostasis as the most apical molecular events leading to cell death in hypericin-photosensitized cells. Downstream of the ER-Ca2+ emptying, both caspase-dependent and -independent pathways are activated to ensure cell demise. The induction of apoptosis as a cell death modality is dependent on the availability of proapopototic Box and Bak proteins, which are essential effectors of the mitochondrial outer membrane permeabilization (MOMP) and subsequent caspase activation. In Bax(-/-)/Bak(-/-) cells a nonapoptotic pathway dependent on sustained autophagy commits the oxidatively damaged cells to death. These results argue that the decision to die in this paradigm of oxidative stress is taken upstream of Bax-dependent MOMP and that the irreversible photodamage to the ER induced by hypericin-PDT acts as a trigger for an autophagic cell death pathway in apoptosis-deficient cells.