Bcl-2 antagonists interact synergistically with bortezomib in DLBCL cells in association with JNK activation and induction of ER stress.
Bcl-2 antagonists interact synergistically with bortezomib in DLBCL cells in association with JNK activation and induction of ER stress.
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DOI：
10.4161/cbt.8.9.8131
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发表时间：
2009-05
影响因子：
3.6
通讯作者：
Grant S
中科院分区：
文献类型：
--
作者：
Dasmahapatra G;Lembersky D;Rahmani M;Kramer L;Friedberg J;Fisher RI;Dent P;Grant S
在GC和ABC型人弥漫性淋巴细胞性B细胞淋巴瘤(DLBCL)细胞中，研究了蛋白酶体抑制剂Bortezomib和小分子Bcl2拮抗剂之间的相互作用机制。同时或连续暴露于无毒性或最小毒性浓度的Bortezomib或其他蛋白酶体抑制剂以及HA14-1或棉酚，可显著增加GC和ABC类型细胞的Bax/Bak构象改变/易位、细胞色素c释放、caspase激活和协同诱导凋亡。这些事件与应激激酶jnk的激活和内质网应激诱导的证据(例如eif2caspase-2和-4的α磷酸化，以及GRP78的上调)有关。药理学或遗传学(如shRNA敲除)阻断JNK信号可减弱HA14-1/bortezomib的致死性和内质网应激诱导。内质网应激途径的遗传破坏(例如，在表达caspase-4shRNA或dN-eIF2α的细胞中)显著降低致死性。该方案的毒性与ROS的生成无关。最后，HA14-1显著增加了Bortezomib介导的JNK激活、内质网应激诱导和对Bortezomib耐药细胞的致死率。总之，这些发现表明，小分子Bcl2拮抗剂通过增强JNK活性和内质网应激诱导，促进了Bortezomib介导的DLBCL细胞线粒体损伤和致死性。他们还提出了这样一种策略可能在不同的DLBCL亚型(例如GC或ABC)以及对博替佐米耐药的疾病中有效的可能性。
Mechanisms underlying interactions between the proteasome inhibitor bortezomib and small molecule Bcl-2 antagonists were examined in GC- and ABC-type human DLBCL (diffuse lymphocytic B-cell lymphoma) cells. Concomitant or sequential exposure to non- or minimally toxic concentrations of bortezomib or other proteasome inhibitors and either HA14-1 or gossypol resulted in a striking increase in Bax/Bak conformational change/translocation, cytochrome c release, caspase activation and synergistic induction of apoptosis in both GC- and ABC-type cells. These events were associated with a sharp increase in activation of the stress kinase JNK and evidence of ER stress induction (e.g., eIF2α phosphorylation, activation of caspases-2 and -4, and Grp78 upregulation). Pharmacologic or genetic (e.g., shRNA knockdown) interruption of JNK signaling attenuated HA14-1/bortezomib lethality and ER stress induction. Genetic disruption of the ER stress pathway (e.g., in cells expressing caspase-4 shRNA or DN-eIF2α) significantly attenuated lethality. The toxicity of this regimen was independent of ROS generation. Finally, HA14-1 significantly increased bortezomib-mediated JNK activation, ER stress induction, and lethality in bortezomib-resistant cells. Collectively these findings indicate that small molecule Bcl-2 antagonists promote bortezomib-mediated mitochondrial injury and lethality in DLBCL cells in association with enhanced JNK activation and ER stress induction. They also raise the possibility that such a strategy may be effective in different DLBCL sub-types (e.g., GC- or ABC), and in bortezomib-resistant disease.
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