IMB-6G, a novel N-substituted sophoridinic acid derivative, induces endoplasmic reticulum stress-mediated apoptosis via activation of IRE1α and PERK signaling.
IMB-6G, a novel N-substituted sophoridinic acid derivative, induces endoplasmic reticulum stress-mediated apoptosis via activation of IRE1α and PERK signaling.
复制标题
IMB-6G 是一种新型 N 取代槐啶酸衍生物，通过激活 IRE1alpha 和 PERK 信号传导诱导内质网应激介导的细胞凋亡。
DOI：
10.18632/oncotarget.8184
复制
发表时间：
2016-04-26
期刊：
影响因子：
--
通讯作者：
Song D
中科院分区：
文献类型：
--
作者：
Zhang N;Bi C;Liu L;Dou Y;Tang S;Pang W;Deng H;Song D
苦豆子酸衍生物因其在癌症治疗中的潜在作用而受到广泛关注。IMB-6G是一种新型的N-取代苦参碱酸衍生物，对肿瘤细胞具有很强的细胞毒作用。在本研究中，我们研究了IMB-6G对人肝癌细胞的抗肿瘤作用，并探讨了其作用机制。我们发现IMB-6G抑制HepG2和SMMC7721细胞的生长并诱导线粒体依赖性的细胞凋亡。对IMB-6G诱导细胞凋亡的分子机制分析表明，IMB-6G诱导内质网应激激活。肝细胞癌细胞与IMB-6G孵育后，诱导细胞凋亡前的BiP和CHOP水平升高。进一步的研究表明，IMB-6G激活了肝癌细胞中的IRE1ATF6和PERK通路，但不能激活α通路。此外，IRE1JNK的沉默显著地阻断了α-6G诱导的促凋亡信号转导。重要的是，阻断CHOP使肝癌细胞对IMB-6G通过失活Bim、PUMA和Bax诱导的细胞凋亡变得敏感。因此，IRE1、α-ASK1和PERK-CHOP通路可能是IMB-6G诱导细胞凋亡的一个新的分子机制。总之，我们的研究表明，IMB-6G通过激活IRE1、α和PERK通路来诱导内质网应激介导的细胞凋亡。我们的发现为IMB-6G在肝癌治疗中的潜在应用提供了理论基础。
Sophoridinic acid derivatives have received considerable attentions for their potencies in cancer therapy. IMB-6G is a novel N-substituted sophoridinic acid derivative with potent cytotoxicity against tumor cells. In the present study, we explored the antitumor abilities of IMB-6G in human hepatocellular carcinoma (HCC) cells and investigated the underlying mechanisms. We found that IMB-6G inhibited cell growth and induced mitochondrial-dependent apoptosis in HepG2 and SMMC7721 cells. Analyses of the molecular mechanism of IMB-6G-induced apoptosis indicated IMB-6G induced endoplasmic reticulum (ER) stress activation. Incubation of HCC cells with IMB-6G induced increase in Bip and CHOP levels, which precede induction of apoptosis. Further study showed IMB-6G activated IRE1α and PERK pathways but did not stimulated ATF6 pathway in HCC cells. Moreover, silencing of IRE1α dramatically abrogated IMB-6G-induced pro-apoptotic ASK1-JNK signaling. Importantly, interruption of CHOP rendered HCC cells sensitive to IMB-6G-induced apoptosis via inactivation of Bim, PUMA and Bax. Thus, the IRE1α-ASK1 and PERK-CHOP pathways may be a novel molecular mechanism of IMB-6G-induced apoptosis. Collectively, our study demonstrates that IMB-6G induces ER stress-mediated apoptosis by activating IRE1α and PERK pathways. Our findings provide a rationale for the potential application of IMB-6G in HCC therapy.
登录
查看更多内容
影响因子：
7.3
作者：
Bean GR;Ganesan YT;Dong Y;Takeda S;Liu H;Chan PM;Huang Y;Chodosh LA;Zambetti GP;Hsieh JJ;Cheng EH
通讯作者：
Cheng EH
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
82.9
作者：
Iwawaki, T;Akai, R;Miura, M
通讯作者：
Miura, M
影响因子：
5.6
作者：
Ma, YJ;Brewer, JW;Hendershot, LM
通讯作者：
Hendershot, LM
促红细胞生成素激活的 c-Jun N 末端蛋白激酶 1 磷酸化 Bcl 相关死亡蛋白 (Bad)，有助于促红细胞生成素依赖性细胞的存活。
DOI：
10.1016/j.biocel.2010.11.011
发表时间：
2011-03
影响因子：
4
作者：
Deng, Hongbin;Zhang, Jingpu;Yoon, Taewon;Song, Danqing;Li, Diandong;Lin, Anning
通讯作者：
Lin, Anning