Autophagy-mediated HMGB1 release antagonizes apoptosis of gastric cancer cells induced by vincristine via transcriptional regulation of Mcl-1
Autophagy-mediated HMGB1 release antagonizes apoptosis of gastric cancer cells induced by vincristine via transcriptional regulation of Mcl-1
复制标题
自噬介导的 HMGB1 释放通过 Mcl-1 转录调控拮抗长春新碱诱导的胃癌细胞凋亡
DOI：
10.4161/auto.8.1.18319
复制
发表时间：
2012-01-01
期刊：
影响因子：
13.3
通讯作者：
Zhang, Xu Dong
中科院分区：
文献类型：
--
作者：
Zhan, ZhenZhen;Li, Qun;Zhang, Xu Dong
众所周知，自噬相关的HMGB1的释放可以保护癌细胞免受许多化疗药物的影响。然而，具体的分子机制(S)在很大程度上仍然不清楚。我们在本研究中发现，释放到细胞外间隙的HMGB1通过转录上调Mcl-1来保护微管靶向药物长春新碱诱导的胃癌细胞凋亡。细胞外HMGB1似乎对自噬介导的凋亡抑制是必不可少的，因为siRNA下调HMGB1或抑制其释放取消了自噬的保护作用。值得注意的是，长春新碱通过转录增加上调Mcl-1mRNA的表达，但不改变Mcl-1蛋白的表达水平。抑制HMGB1的释放阻断了Mcl-1转录本的增加，并在蛋白水平上导致Mcl-1的表达减少，表明HMGB1介导的信号转导是Mcl-1转录上调所必需的。这似乎对维持暴露于长春新碱的胃癌细胞生存所需的足够的Mcl-1蛋白表达至关重要。在重组HMGB1处理的胃癌细胞中，证实了细胞外HMGB1对Mcl-1转录调控的影响。综上所述，这些结果证实HMGB1介导的Mcl-1转录上调是自噬保护长春新碱诱导的胃癌细胞凋亡的重要机制。
Autophagy-associated release of HMGB1 is known to protect cancer cells from many chemotherapeutics. However, the detailed molecular mechanism(s) responsible remains largely undefined. We show in this study that HMGB1 released into the extracellular space protects gastric cancer cells from apoptosis induced by the microtubule-targeting drug vincristine through transcriptional upregulation of Mcl-1. Extracellular HMGB1 appeared essential for autophagy-mediated inhibition of apoptosis, in that siRNA knockdown of HMGB1 or inhibition of its release abolished the protective effect of autophagy. Strikingly, vincristine upregulated the Mcl-1 mRNA expression through a transcriptional increase, but did not alter the expression levels of the Mcl-1 protein. Inhibition of HMGB1 release blocked the increase in the Mcl-1 transcript and caused reduction in Mcl-1 at the protein level, indicating that HMGB1-mediated signaling was necessary for transcriptional upregulation of Mcl-1. This seemed critical for maintaining sufficient Mcl-1 protein expression required for survival of gastric cancer cells exposed to vincristine. The effect of extracellular HMGB1 on transcriptional regulation of Mcl-1 was confirmed in gastric cancer cells treated with recombinant HMGB1. Taken together, these results identify HMGB1-mediated upregulation of Mcl-1 transcription as an important mechanism by which autophagy protects gastric cancer cells from apoptosis induced by vincristine.