The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006
The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006
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DOI：
10.1038/sj.onc.1208841
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发表时间：
2005-10-20
期刊：
影响因子：
8
通讯作者：
Adjei, AA
中科院分区：
文献类型：
--
作者：
Yu, CR;Bruzek, LM;Adjei, AA
BAY 43-9006是一种靶向Raf的多激酶抑制剂，可在体外阻止肿瘤细胞增殖，并在体内抑制多种人类肿瘤异种移植物。BAY 43-9006的作用机制尚未完全确定。本研究探讨了BAY 43-9006对Bcl-2家族成员Mcl-1抗凋亡的影响。用BAY 43-9006治疗A549肺癌细胞可降低Mcl-1水平，且呈时间和剂量依赖性，不影响其他Bcl-2家族成员。在ACHN（肾细胞）、HT-29（结肠细胞）、MDA-MB-231（乳腺细胞）、KMCH（胆管癌）、Jurkat（急性t细胞白血病）、K562（慢性骨髓性白血病）和MEC-2（慢性淋巴细胞白血病）细胞中也观察到类似的BAY 43-9006诱导的Mcl-1下调。Mcl-1 mRNA水平在BAY 43-9006处理的细胞中没有变化。相反，BAY 43-9006增强了蛋白酶体介导的Mcl-1降解。Mcl-1下调后，线粒体细胞色素c释放和caspase激活，以及对其他促凋亡药物的敏感性增强。caspase抑制剂Boc-D-fmk抑制BAY 43-9006诱导的caspase激活，但不抑制细胞色素c的释放。相反，Mcl-1过表达抑制了细胞色素c的释放和BAY 43-9006诱导的细胞凋亡的其他特征。相反，短发夹RNA下调Mcl-1可增强BAY 43-9006诱导的细胞凋亡。综上所述，这些发现表明药物诱导的Mcl-1下调参与了BAY 43-9006的促凋亡作用。
BAY 43-9006, a multikinase inhibitor that targets Raf, prevents tumor cell proliferation in vitro and inhibits diverse human tumor xenografts in vivo. The mechanism of action of BAY 43-9006 remains incompletely defined. In the present study, the effects of BAY 43-9006 on the antiapoptotic Bcl-2 family member Mcl-1 were examined. Treatment of A549 lung cancer cells with BAY 43-9006 diminished Mcl-1 levels in a time- and dose-dependent manner without affecting other Bcl-2 family members. Similar BAY 43-9006-induced Mcl-1 downregulation was observed in ACHN (renal cell), HT-29 (colon), MDA-MB-231 (breast), KMCH (cholangiocarcinoma), Jurkat (acute T-cell leukemia), K562 (chronic myelogenous leukemia) and MEC-2 ( chronic lymphocytic leukemia) cells. Mcl-1 mRNA levels did not change in BAY 43-9006-treated cells. Instead, BAY 43-9006 enhanced proteasome-mediated Mcl-1 degradation. This Mcl-1 downregulation was followed by mitochondrail cytochrome c release and caspase activation as well as enhanced sensitivity to other proapoptotic agents. The caspase inhibitor Boc-D-fmk inhibited BAY 43-9006-induced caspase activation but not cytochrome c release. In contrast, Mcl-1 overexpression inhibited cytochrome c release and other features of BAY 43-9006-induced apoptosis. Conversely, Mcl-1 downregulation by short hairpin RNA enhanced BAY 43-9006-induced apoptosis. Collectively, these findings demonstrate that drug-induced Mcl-1 downregulation contributes to the proapoptotic effects of BAY 43-9006.