Raf-1 and Bcl-2 induce distinct and common pathways that contribute to breast cancer drug resistance.
Raf-1 and Bcl-2 induce distinct and common pathways that contribute to breast cancer drug resistance.
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发表时间：
2003-03
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通讯作者：
Julianne M Davis;P. Navolanic;C. Weinstein-Oppenheimer;L. Steelman;Wei Hu;M. Konopleva;M. Blagosklonny;J. McCubrey
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作者：
Julianne M Davis;P. Navolanic;C. Weinstein-Oppenheimer;L. Steelman;Wei Hu;M. Konopleva;M. Blagosklonny;J. McCubrey
Bcl-2的过表达在白血病和其他易复发肿瘤的耐药性发展中起作用。Raf亚型是一种丝氨酸/苏氨酸激酶，在许多生长因子和有丝分裂原启动的级联反应中作为信号转导子。Raf亚型的激活与白血病的耐药性有关。在这项研究中，我们研究了Bcl-2和Raf-1对阿霉素诱导的MCF-7乳腺癌细胞生长抑制的影响。在没有阿霉素的情况下，Bcl-2或组成型活性形式的Raf-1在MCF-7细胞中的过表达不影响增殖率。Bcl-2过表达增加MCF-7细胞在2天、5天和8周试验中对阿霉素的耐药性。单个MCF/Bcl-2克隆的阿霉素敏感性分析显示，阿霉素抗性与Bcl-2过表达水平呈正相关。组成型活性Raf-1的过表达也增加了对阿霉素的耐药性。在过表达Bcl-2的MCF-7细胞中诱导Raf-1活性比在缺乏Bcl-2过表达的MCF-7细胞中诱导Raf-1活性导致更大的阿霉素抗性。此外，P-糖蛋白的mRNA水平增加MCF-7细胞过表达的组成型活性的Raf-1。过表达组成型活性Raf-1的MCF-7细胞也对紫杉醇更耐药，紫杉醇与阿霉素一样是P-糖蛋白的底物。这些观察结果表明Raf-1和Bcl-2癌基因在多柔比星生长抑制抗性中的作用既独立又重叠。
Overexpression of Bcl-2 plays a role in the development of drug resistance in leukemia and other apoptosis-prone tumors. Raf isoforms areserine/threonine kinases that act as signal transducers in cascades initiated by many growth factors and mitogens. Raf isoform activation has been linked to drug resistance in leukemia. In this study we investigated effects of Bcl-2 and Raf-1 on doxorubicin-induced growth inhibition of MCF-7 breast cancer cells. In the absence of doxorubicin, overexpression of Bcl-2 or a constitutively active form of Raf-1 in MCF-7 cells did not affect proliferation rate. Overexpression of Bcl-2 increased resistance of MCF-7 cells to doxorubicin in 2-day, 5-day, and 8-week assays. Analysis of doxorubicin sensitivity of individual MCF/Bcl-2 clones showed that doxorubicin resistance was positively correlated with level of Bcl-2 overexpression. Overexpression of constitutively active Raf-1 also increased resistance to doxorubicin. Induction of Raf-1 activity in MCF-7 cells overexpressing Bcl-2 resulted in greater doxorubicin resistance than induction of Raf-1 activity in MCF-7 cells lacking Bcl-2 overexpression. Furthermore, levels of P-glycoprotein mRNA were increased in MCF-7 cells overexpressing a constitutively active Raf-1. MCF-7 cells overexpressing constitutively active Raf-1 were also more resistant to paclitaxel, which, like doxorubicin, is a substrate of P-glycoprotein. These observations suggest both independent and overlapping roles for Raf-1 and Bcl-2 oncogenes in the resistance to growth inhibition by doxorubicin.