HMGB1-mediated autophagy attenuates gemcitabine-induced apoptosis in bladder cancer cells involving JNK and ERK activation.
HMGB1-mediated autophagy attenuates gemcitabine-induced apoptosis in bladder cancer cells involving JNK and ERK activation.
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HMGB1 介导的自噬减弱吉西他滨诱导的膀胱癌细胞凋亡，涉及 JNK 和 ERK 激活
DOI：
10.18632/oncotarget.17796
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发表时间：
2017-09-22
期刊：
影响因子：
--
通讯作者：
He W
中科院分区：
文献类型：
--
作者：
Yin H;Yang X;Gu W;Liu Y;Li X;Huang X;Zhu X;Tao Y;Gou X;He W
高迁移率族蛋白1(HMGB1)被发现在几种癌症的化疗过程中介导自噬。然而，HMGB1是否在膀胱癌的自噬和化疗耐药中发挥作用尚不清楚。在这份报告中，30例原发膀胱癌组织中HMGB1的表达高于其匹配的癌旁非肿瘤组织。吉西他滨在诱导细胞凋亡的同时，也诱导了膀胱癌T24和BIU-87细胞HMGB1的表达和自噬。SiRNA抑制HMGB1的表达可增强吉西他滨诱导的细胞凋亡。HMGB1 siRNA或自噬抑制剂抑制吉西他滨诱导的自噬。此外，吉西他滨可激活c-jun氨基末端激酶(JNK)、细胞外调节蛋白激酶(ERK)和Bcl2的磷酸化，阻断ERK和JNK可抑制细胞自噬，增加细胞凋亡率。有趣的是，抑制HMGB1的表达减弱了吉西他滨诱导的ERK和JNK的激活以及Bcl2的磷酸化。因此，我们的结果表明，吉西他滨在通过细胞凋亡杀死膀胱癌细胞的同时，也诱导了HMGB1介导的JNK和ERK的细胞保护性自噬，以抵消吉西他滨的细胞毒性，针对这一途径的干预可能会提高吉西他滨对膀胱癌的抗癌效果。
High-mobility group box 1 (HMGB1) has been found to mediate autophagy during chemotherapy in several cancers. However, whether HMGB1plays a role in autophagy and chemoresistance in bladder cancer is elusive. In this report, HMGB1 expression was found to be increased in 30 primary bladder cancer tissue specimens compared to their matched adjacent non-tumor tissues. While gemcitabine induced apoptotic cell death, it also induced HMGB1 expression and autophagy in bladder cancer T24 and BIU-87 cells. Suppressing HMGB1 expression with siRNA strongly potentiated gemcitabine-induced apoptosis. HMGB1 siRNA or autophagy inhibitors suppressed gemcitabine-induced autophagy. Further, gemcitabine activated c-Jun N-terminal kinase (JNK) and extracellular regulated protein kinase (ERK) and Bcl-2 phosphorylation, and blocking ERK and JNK inhibited autophagy and increased apoptosis in gemcitabine-treated cells. Interestingly, suppressing HMGB1 expression attenuated gemcitabine-induced ERK and JNK activation and Bcl-2 phosphorylation. Thus, our results suggest that while gemcitabine kills bladder cancer cells through apoptosis, a cytoprotective autophagy is also induced involving HMGB1-mediated JNK and ERK to counteract the cytotoxicity of gemcitabine, and intervention targeting this pathway may improve the anticancer efficacy of gemcitabine against bladder cancer.
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影响因子：
6
作者：
Kumar P;Zhang DM;Degenhardt K;Chen ZS
通讯作者：
Chen ZS
影响因子：
12.4
作者：
Kang R;Tang D;Schapiro NE;Livesey KM;Farkas A;Loughran P;Bierhaus A;Lotze MT;Zeh HJ
通讯作者：
Zeh HJ
对抗癌疗法的耐药性的进化。
影响因子：
2
作者：
Foo, Jasmine;Michor, Franziska
通讯作者：
Michor, Franziska
影响因子：
13.3
作者：
He, Weiyang;Wang, Qiong;Lin, Yong
通讯作者：
Lin, Yong
DOI：
10.1158/1078-0432.ccr-13-0495
发表时间：
2013-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Kang R;Zhang Q;Zeh HJ 3rd;Lotze MT;Tang D
通讯作者：
Tang D