Dual induction of apoptotic and autophagic cell death by targeting survivin in head neck squamous cell carcinoma.
Dual induction of apoptotic and autophagic cell death by targeting survivin in head neck squamous cell carcinoma.
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通过靶向头颈鳞状细胞癌中的生存素双重诱导细胞凋亡和自噬性细胞死亡
DOI：
10.1038/cddis.2015.139
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发表时间：
2015-05-28
影响因子：
9
通讯作者：
Sun ZJ
中科院分区：
文献类型：
--
作者：
Zhang L;Zhang W;Wang YF;Liu B;Zhang WF;Zhao YF;Kulkarni AB;Sun ZJ
生存素在头颈部鳞状细胞癌（HNSCC）患者中广泛表达，并与生存率低和化疗耐药性相关。Sepantronium bromide（YM 155）是一种选择性生存素抑制剂，通过诱导各种类型癌症中的细胞凋亡和自噬而显示出有效的抗肿瘤活性。然而，YM 155在HNSCC中的疗效和潜在机制尚不清楚。本研究表明，在人HNSCC组织中，Survivin过表达与p-S6、p-Rb和LAMP 2正相关，而与自噬标志物LC 3负相关。体外研究表明，YM 155以线粒体和死亡受体依赖的方式触发HNSCC细胞凋亡。该治疗还通过上调Beclin 1显著增强了自噬，导致细胞死亡。YM 155不仅下调survivin的表达，而且在体外和体内显著抑制mTOR信号通路的激活。YM 155在CAL 27异种移植和转基因HNSCC小鼠模型中通过延迟肿瘤发作和抑制肿瘤生长显示出有效的抗肿瘤活性。此外，在HNSCC异种移植模型中，YM 155与多西他赛组合比单独的任一种治疗更好地促进肿瘤消退，而不引起相当大的体重减轻。总的来说，通过YM 155靶向生存素可以通过增加凋亡和自噬细胞死亡以及抑制促生存途径来有益于HNSCC治疗。
Survivin is ubiquitously expressed in patients with head neck squamous cell carcinoma (HNSCC) and is associated with poor survival and chemotherapy resistance. Sepantronium bromide (YM155) is a selective survivin suppressant that exhibits potent antitumor activities by inducing apoptosis and autophagy in various types of cancer. However, the curative effects and underlying mechanisms of YM155 in HNSCC remain unclear. This study showed that survivin overexpression positively correlated with p-S6, p-Rb and LAMP2 but negatively correlated with the autophagic marker LC3 in human HNSCC tissues. In vitro studies revealed that YM155 triggered apoptosis of HNSCC cells in mitochondria and death receptor-dependent manner. The treatment also significantly enhanced autophagy by upregulating Beclin1, which led to cell death. YM155 not only downregulated the expression of survivin but also remarkably suppressed the activation of the mTOR signaling pathway in vitro and in vivo. YM155 displayed potent antitumor activities in both CAL27 xenograft and transgenic HNSCC mice models by delaying tumor onset and suppressing tumor growth. Furthermore, YM155 combined with docetaxel promoted tumor regression better than either treatment alone without causing considerable body weight loss in the HNSCC xenograft models. Overall, targeting survivin by YM155 can benefit HNSCC therapy by increasing apoptotic and autophagic cell death, and suppressing prosurvival pathways.