Endoplasmic reticulum stress mediates radiation-induced autophagy by perk-eIF2alpha in caspase-3/7-deficient cells.
Endoplasmic reticulum stress mediates radiation-induced autophagy by perk-eIF2alpha in caspase-3/7-deficient cells.
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作者：
Kim, K. W.;Moretti, L.;Mitchell, L. R.;Jung, D. K.;Lu, B.
由于细胞凋亡缺陷限制了抗癌药物的疗效，自噬已被认为是一种新的放射治疗增强策略。我们先前在体外和体内研究表明，抑制caspase-3/7可以诱导自噬并提高放射敏感性。因此，我们进一步研究了辐射触发caspase-3/7缺陷细胞自噬的机制，并发现内质网应激参与其中。内质网激活一条生存途径，即未折叠蛋白反应，其中涉及内质网定位的跨膜蛋白PERK、IRE1和ATF6。在这项研究中，我们发现在caspase-3/7双基因敲除细胞中，PERK对于辐射诱导的自噬和辐射敏感性是必不可少的。照射这些细胞后，磷酸化的elF2α的表达增加。在服用衣霉素(TM)后也看到了类似的结果，衣霉素是一种众所周知的内质网应激源。重要的是，我们发现，在MCF-7乳腺癌细胞中，TM与辐射一起使用，增强了辐射敏感性。MCF-7乳腺癌细胞缺乏功能性caspase-3，并且对许多抗癌药物相对耐药。我们的发现揭示了内质网应激是辐射诱导caspase-3/7缺陷细胞自噬的一种新的潜在机制，并作为一种潜在的策略来最大化乳腺癌放射治疗的效率。
Since apoptosis defects limit efficacy of anti-cancer agents, autophagy has been proposed as a novel strategy for radiotherapy enhancement. We previously showed that caspase-3/7 inhibition induces autophagy and promotes radiosensitivity in vitro and in vivo. Therefore, we further investigated the mechanism by which radiation triggers autophagy in caspase-3/7 deficient cells, and found the involvement of Endoplasmic Reticulum (ER) stress. The ER activates a survival pathway, the unfolded protein response, which involves ER-localized transmembrane proteins PERK, IRE1, and ATF6. In this study, we found that PERK is essential for radiation-induced autophagy and radiosensitivity in caspase-3/7 double-knockout cells. Irradiation of these cells increased expression of phosphorylated-elf2α. Similar results were seen following administration of tunicamycin (TM), a well known ER stressor. Importantly, we found that the administration of TM with radiation in MCF-7 breast cancer cells, which are lacking functional caspase-3 and relatively resistant to many anti-cancer agents, enhances radiation sensitivity. Our findings reveal ER stress as a novel potential mechanism of radiation-induced autophagy in caspase-3/7 deficient cells and as a potential strategy to maximize efficiency of radiation therapy in breast cancer.
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DOI：
10.1083/jcb.152.4.657
发表时间：
2001-02-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Mizushima N;Yamamoto A;Hatano M;Kobayashi Y;Kabeya Y;Suzuki K;Tokuhisa T;Ohsumi Y;Yoshimori T
通讯作者：
Yoshimori T
影响因子：
4.8
作者：
Ding, Wen-Xing;Ni, Hong-Min;Yin, Xiao-Ming
通讯作者：
Yin, Xiao-Ming
影响因子：
11.2
作者：
Daido, S;Yamamoto, A;Kondo, Y
通讯作者：
Kondo, Y
影响因子：
4.2
作者：
Dahmer, MK
通讯作者：
Dahmer, MK
影响因子：
5.6
作者：
Ma, YJ;Brewer, JW;Hendershot, LM
通讯作者：
Hendershot, LM