The proteasome inhibitor bortezomib sensitizes cells to killing by death receptor ligand TRAIL via BH3-only proteins Bik and Bim
The proteasome inhibitor bortezomib sensitizes cells to killing by death receptor ligand TRAIL via BH3-only proteins Bik and Bim
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DOI：
10.1158/1535-7163.mct-04-0260
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发表时间：
2005-03
影响因子：
5.7
通讯作者：
Malti Nikrad;T. Johnson;Hamsa Puthalalath;L. Coultas;Jerry M. Adams;A. Kraft
中科院分区：
文献类型：
--
作者：
Malti Nikrad;T. Johnson;Hamsa Puthalalath;L. Coultas;Jerry M. Adams;A. Kraft
以前，我们发现蛋白酶体抑制剂bortezalone/Velcade（以前的PS-341）与蛋白质肿瘤坏死因子α相关凋亡诱导配体（TRAIL）（某些死亡受体的配体）协同作用，诱导前列腺癌和结肠癌细胞系的凋亡。由于细胞凋亡通常由Bcl-2家族的BH 3-only蛋白触发，因此我们探索了硼替佐米通过上调其水平而促进细胞凋亡的假设。事实上，硼替佐米在多种细胞系中诱导Bik和/或Bim的增加，但不显著地诱导另外两种仅BH 3蛋白（Puma和Bid）或其他家族成员（Bax、巴克、Bcl-2和Bcl-xL）的增加。Bik水平的增加似乎反映了硼替佐米对其蛋白酶体介导的降解的抑制。重要的是，Bik和Bim似乎是硼替佐米促凋亡功能的核心，因为Bik和Bim基因均被破坏的小鼠胚胎成纤维细胞对其细胞毒性作用不敏感。类似地，硼替佐米和TRAIL在杀死人前列腺癌细胞中的协同作用在Bik和Bim均通过RNA干扰下调的细胞中受损。硼替佐米通过Bcl-2家族调节的线粒体途径起作用的进一步证据是，作用于Bcl-2下游的APAF-1的缺乏也阻断了其凋亡作用。这些结果暗示BH 3-only蛋白，特别是Bik和Bim，作为硼替佐米抗肿瘤作用的重要介质，并建立它们在增强TRAIL诱导的细胞凋亡中的作用。
Previously, we showed that the proteasome inhibitor bortezomib/Velcade (formerly PS-341) synergizes with the protein tumor necrosis factor α–related apoptosis-inducing ligand (TRAIL), a ligand for certain death receptors, to induce apoptosis in cell lines derived from prostate and colon cancers. Because apoptosis is often triggered by BH3-only proteins of the Bcl-2 family, we have explored the hypothesis that bortezomib contributes to the apoptosis by up-regulating their levels. Indeed, bortezomib induced increases of Bik and/or Bim in multiple cell lines but not notably of two other BH3-only proteins (Puma and Bid) nor other family members (Bax, Bak, Bcl-2, and Bcl-xL). The increase in Bik levels seems to reflect inhibition by bortezomib of its proteasome-mediated degradation. Importantly, both Bik and Bim seem central to the proapoptotic function of bortezomib, because mouse embryo fibroblasts in which the genes for both Bik and Bim had been disrupted were refractory to its cytotoxic action. Similarly, the synergy between bortezomib and TRAIL in killing human prostate cancer cells was impaired in cells in which both Bik and Bim were down-regulated by RNA interference. Further evidence that bortezomib acts through the mitochondrial pathway regulated by the Bcl-2 family is that deficiency for APAF-1, which acts downstream of Bcl-2, also blocked its apoptotic effect. These results implicate BH3-only proteins, in particular both Bik and Bim, as important mediators of the antitumor action of bortezomib and establish their role in its enhancement of TRAIL-induced apoptosis.