ROS-independent JNK activation and multisite phosphorylation of Bcl-2 link diallyl tetrasulfide-induced mitotic arrest to apoptosis
ROS-independent JNK activation and multisite phosphorylation of Bcl-2 link diallyl tetrasulfide-induced mitotic arrest to apoptosis
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DOI：
10.1093/carcin/bgs240
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发表时间：
2012-11-01
期刊：
影响因子：
4.7
通讯作者：
Diederich, Marc
中科院分区：
文献类型：
--
作者：
Kelkel, Mareike;Cerella, Claudia;Diederich, Marc
大蒜衍生的有机硫化合物，包括二烯丙基多硫化物，具有多种有益健康的特性，最近的报道甚至指出，二烯丙基多硫化物由于具有选择性的抗增殖作用，在癌症治疗中具有潜在的化学预防和治疗作用。在这方面，二烯丙基三硫化物和四硫化物被报道为早期有丝分裂停止和随后的细胞凋亡的强烈诱导剂，但潜在的分子机制和这两个事件之间的联系尚未完全阐明。我们的数据显示，二烯丙基四硫化物的作用不依赖于活性氧物种，而微管蛋白是其主要的细胞靶标之一。微管蛋白解聚阻止正常纺锤体微管的形成，从而导致G2/M期停滞。在这里，我们提供了证据，c-jun氨端激酶在二烯丙基四硫化物治疗后被早期激活，介导了抗凋亡蛋白B细胞淋巴瘤2的多位点磷酸化和随后的蛋白分解。由于后者伴随着细胞凋亡的开始而发生，并且化学c-jun氨基末端激酶抑制剂SP600125不仅阻止了B细胞淋巴瘤2的磷酸化和蛋白分解，而且还阻止了二烯丙基四硫治疗后的细胞凋亡，我们认为这些c-jun氨基末端激酶介导的调控B细胞淋巴瘤2是连接早期微管失活和诱导凋亡的缺失环节。
Garlic-derived organosulfur compounds including diallyl polysulfides are well known for various health-beneficial properties and recent reports even point to a potential role of diallyl polysulfides as chemopreventive and therapeutic agents in cancer treatment due to their selective antiproliferative effects. In this respect, diallyl tri- and tetrasulfide are reported as strong inducers of an early mitotic arrest and subsequent apoptosis, but the underlying molecular mechanisms and the link between these two events are not yet fully elucidated. Our data revealed that diallyl tetrasulfide acts independently of reactive oxygen species and tubulin represents one of its major cellular targets. Tubulin depolymerization prevents the formation of normal spindle microtubules, thereby leading to G2/M arrest. Here, we provide evidence that c-jun N-terminal kinase, which is activated early in response to diallyl tetrasulfide treatment, mediates multisite phosphorylation and subsequent proteolysis of the anti-apoptotic protein B-cell lymphoma 2. As the latter event occurs concomitantly with the onset of apoptosis and the chemical c-jun N-terminal kinase inhibitor SP600125 not only prevented B-cell lymphoma 2 phosphorylation and proteolysis but also apoptosis following diallyl tetrasulfide treatment, we suggest that these c-jun N-terminal kinase-mediated modulations of B-cell lymphoma 2 represent the missing link connecting early microtubule inactivation to the induction of apoptosis.