Yu Chunrong, Bruzek Laura M, Meng Xue Wei, Gores Gregory J, Carter Christopher A, Kaufmann Scott H, Adjei Alex A
Division of Medical Oncology, Mayo Clinic, 200 First Street. SW, Rochester, MN 55905, USA.
Oncogene. 2005 Oct 20;24(46):6861-9. doi: 10.1038/sj.onc.1208841.
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 mitochondrial 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.
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。BAY 43 - 9006的作用机制仍未完全明确。在本研究中，检测了BAY 43 - 9006对抗凋亡Bcl - 2家族成员Mcl - 1的影响。用BAY 43 - 9006处理A549肺癌细胞，可使Mcl - 1水平呈时间和剂量依赖性降低，而不影响其他Bcl - 2家族成员。在ACHN（肾细胞）、HT - 29（结肠）、MDA - MB - 231（乳腺）、KMCH（胆管癌）、Jurkat（急性T细胞白血病）、K562（慢性粒细胞白血病）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。在经BAY 43 - 900６处理的细胞中，Mcl - 1 mRNA水平没有变化。相反，BAY 43 - 9006增强了蛋白酶体介导的Mcl - 1降解。这种Mcl - 1下调随后伴随着线粒体细胞色素c释放和半胱天冬酶激活，以及对其他促凋亡剂的敏感性增强。半胱天冬酶抑制剂Boc - D - fmk抑制了BAY 43 - 9006诱导的半胱天冬酶激活，但不抑制细胞色素c释放。相反，Mcl - 1过表达抑制了细胞色素c释放和BAY 43 - 9006诱导的凋亡的其他特征。相反，短发夹RNA介导的Mcl - 1下调增强了BAY 43 - 9006诱导的凋亡。总的来说，这些发现表明药物诱导的Mcl - 1下调有助于BAY 43 - 9006的促凋亡作用。
