Cucurbitacin I induces cancer cell death through the endoplasmic reticulum stress pathway
Cucurbitacin I induces cancer cell death through the endoplasmic reticulum stress pathway
复制标题
葫芦素 I 通过内质网应激途径诱导癌细胞死亡
DOI：
10.1002/jcb.27570
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发表时间：
2019-02-01
影响因子：
4
通讯作者：
Zhu, Ling
中科院分区：
文献类型：
--
作者：
Li, He;Chen, Hongying;Zhu, Ling
内质网应激（ERS）通常与肿瘤的发生和进展有关，最近发现抗癌药物可以诱导内质网应激。 Cucurbitacin-I 通过抑制信号转导器和转录 3 通路激活剂诱导细胞凋亡并触发自噬性细胞死亡，从而显示出有效的抗癌作用。目前尚不清楚 ERS 是否介导葫芦素-I 诱导的癌细胞死亡。在这里，我们研究了 ERS 在葫芦素-I 处理的 SKOV3 卵巢癌细胞和 PANC-1 胰腺癌细胞中的作用。我们证实葫芦素-I 通过激活肌醇需要酶 1 (IRE1) 和蛋白激酶 R 样内质网激酶 (PERK) 以及 PERK 下游因子，包括 IRE1 和 C/EBP 同源蛋白，但不激活转录因子 6 (ATF6) 途径，导致细胞死亡并引起过量的 ERS 水平，这与 Bax 的增加是平行的 和 caspase-12 依赖性 ERS 相关的细胞凋亡、自噬和自噬通量水平以及不依赖 caspase 的非凋亡细胞死亡。此外，ERS 抑制剂 4-苯基丁酸酯可抑制葫芦素 I 诱导的细胞凋亡、自噬、自噬流和自噬细胞死亡。同时，ERS与葫芦素-I诱导的活性氧和Ca(2+)之间存在正相关关系。我们的结果表明，葫芦素-I 通过过量的 ERS 和 CHOP-Bax 和 caspase-12 依赖性 ERS 相关细胞凋亡，以及 ERS 依赖性自噬、自噬流和不依赖 caspase 的非凋亡细胞死亡诱导癌细胞死亡。这些新颖的信号传导见解可能有助于在肿瘤治疗中开发新的、有效的抗癌策略。
Endoplasmic reticulum stress (ERS) is usually involved in tumor development and progression, and anticancer agents have recently been recognized to induce ERS. Cucurbitacin-I showed a potent anticancer action by inducing apoptosis through the inhibition of signal transducer and activator of transcription 3 pathway and triggering autophagic cell death. It is not known whether ERS mediates the cancer cell death induced by cucurbitacin-I. Here, we investigated the role of ERS in cucurbitacin-I-treated SKOV3 ovarian cancer cells and PANC-1 pancreatic cancer cells. We confirmed that cucurbitacin-I caused cell death and stirred excessive ERS levels by activating inositol requiring enzyme 1 (IRE1) and protein kinase R-like endoplasmic reticulum kinase (PERK), as well as PERK downstream factors, includingIRE1 and C/EBP homologous protein, but not activating transcription factor 6 (ATF6) pathway, which was in parallel with the increased Bax and caspase-12-dependent ERS-associated apoptosis, autophagy and autophagy flux levels and caspase-independent nonapoptotic cell death. Furthermore, 4-phenylbutyrate, an ERS inhibitor, suppressed cucurbitacin-I-induced apoptosis, autophagy, autophagy flux, and autophagic cell death. Simultaneously, there are positive correlations among ERS and cucurbitacin-I-induced reactive oxygen speciesand Ca (2+). Our results suggested that cucurbitacin-I-induced cancer cell death through the excessive ERS and CHOP-Bax and caspase-12-dependent ERS-associated apoptosis, as well as ERS-dependent autophagy, autophagy flux, and caspase-independent nonapoptotic cell death. These novel signaling insights may be useful for developing new, effective anticancer strategies in oncotherapy.