Inhibition of endoplasmic reticulum (ER) stress sensors sensitizes cancer stem-like cells to ER stress-mediated apoptosis.
Inhibition of endoplasmic reticulum (ER) stress sensors sensitizes cancer stem-like cells to ER stress-mediated apoptosis.
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DOI：
10.18632/oncotarget.10126
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发表时间：
2016-08-09
期刊：
影响因子：
--
通讯作者：
Fujii T
中科院分区：
文献类型：
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作者：
Fujimoto A;Kawana K;Taguchi A;Adachi K;Sato M;Nakamura H;Ogishima J;Yoshida M;Inoue T;Nishida H;Tomio K;Yamashita A;Matsumoto Y;Arimoto T;Wada-Hiraike O;Oda K;Nagamatsu T;Osuga Y;Fujii T
虽然癌症干细胞（CSC）已被牵连的发展，耐药性的抗癌治疗，包括化疗，CSC的化学耐药的机制尚未阐明。本文中，我们从宫颈癌细胞系SiHa中分离出球形（癌干细胞样）细胞，并检查了对化疗诱导的内质网（ER）应激的未折叠蛋白反应（UPR）。我们发现衣霉素诱导的内质网应激介导的细胞凋亡发生在单层细胞，而不是球形形成的细胞。生化分析表明，在衣霉素诱导的ER应激条件下，形成球体的细胞通过IRE 1（XBP-1剪接）的失活和PERK（eIF 2 α磷酸化）分支的激活而转变为促存活信号传导。通过衣霉素+PERK抑制剂（PERKi）处理，球形成细胞中凋亡细胞的比例显著增加，表明PERKi使球形成细胞对衣霉素诱导的凋亡敏感。还已知顺铂诱导ER应激介导的细胞凋亡。低浓度的顺铂不能使成球细胞向凋亡方向转变，尽管IRE 1分支被激活，但PERK没有被激活。经顺铂+IRE 1 α抑制剂（IRE 1 i）处理的球形细胞中发生ER应激介导的凋亡。IRE 1 i与顺铂协同作用，上调eIF 2 α磷酸化，随后诱导球体形成细胞中的CHOP。本研究的结果表明，ER应激传感器的抑制，结合ER应激诱导的化疗，转移癌干细胞样细胞ER应激介导的凋亡。
Although cancer stem cells (CSC) have been implicated in the development of resistance to anti-cancer therapy including chemotherapy, the mechanisms underlying chemo-resistance by CSC have not yet been elucidated. We herein isolated sphere-forming (cancer stem-like) cells from the cervical cancer cell line, SiHa, and examined the unfolded protein reaction (UPR) to chemotherapeutic-induced endoplasmic reticulum (ER) stress. We revealed that tunicamycin-induced ER stress-mediated apoptosis occurred in monolayer, but not sphere-forming cells. Biochemical assays demonstrated that sphere-forming cells were shifted to pro-survival signaling through the inactivation of IRE1 (XBP-1 splicing) and activation of PERK (elF2α phosphorylation) branches under tunicamycin-induced ER stress conditions. The proportion of apoptotic cells among sphere-forming cells was markedly increased by the tunicamycin+PERK inhibitor (PERKi) treatment, indicating that PERKi sensitized sphere-forming cells to tunicamycin-induced apoptosis. Cisplatin is also known to induce ER stress-mediated apoptosis. A low concentration of cisplatin failed to shift sphere-forming cells to apoptosis, although IRE1 branch, but not PERK, was activated. ER stress-mediated apoptosis occurred in sphere-forming cells by the cisplatin+IRE1α inhibitor (IRE1i) treatment. IRE1i, synergistic with cisplatin, up-regulated elF2α phosphorylation, and this was followed by the induction of CHOP in sphere-forming cells. The results of the present study demonstrated that the inhibition of ER stress sensors, combined with ER stress-inducible chemotherapy, shifted cancer stem-like cells to ER stress-mediated apoptosis.