Targeting the Fanconi Anemia/BRCA Pathway Circumvents Drug Resistance in Multiple Myeloma.
Targeting the Fanconi Anemia/BRCA Pathway Circumvents Drug Resistance in Multiple Myeloma.
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DOI：
10.1158/0008-5472.can-09-2616
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发表时间：
2009-12-15
期刊：
影响因子：
11.2
通讯作者：
Dalton, William S.
中科院分区：
文献类型：
--
作者：
Yarde, Danielle N.;Oliveira, Vasco;Dalton, William S.
Fanconi贫血/BRCA（FA/BRCA）DNA损伤修复途径在DNA烷化剂诱导的细胞复制应激反应中起着关键作用，并极大地影响癌症治疗的药物反应。我们最近报道了FA/BRCA基因在人美法仑耐药的多发性骨髓瘤细胞系中的过表达和耐药性的原因。然而，FA/BRCA通路的转录调控尚不清楚。在本报告中，我们首次描述了NF-κ B B亚基RelB/p50作为FA/BRCA通路转录激活因子的新功能。具体来说，我们的发现指出I κ B激酶α的组成性磷酸化和随后FANCD 2表达和功能的改变是导致反复暴露的多发性骨髓瘤细胞中美法仑耐药的潜在事件。通过小干扰RNA抑制NF-κ B、用BMS-345541阻断I κ B激酶复合物或使用蛋白酶体抑制剂硼替佐米显著降低骨髓瘤细胞中FA/BRCA基因表达和FANCD 2蛋白表达，导致DNA损伤修复减少和美法仑敏感性增强。重要的是，我们还发现硼替佐米降低多发性骨髓瘤患者的FA/BRCA基因表达。这些结果首次表明NF-κ B转录调节FA/BRCA通路，并为靶向Fanconi贫血介导的DNA修复以增强骨髓瘤患者的化疗反应和规避耐药性提供了证据。[Cancer Res 2009;69（24）：9367-75]
The Fanconi anemia/BRCA (FA/BRCA) DNA damage repair pathway plays a pivotal role in the cellular response to replicative stress induced by DNA alkylating agents and greatly influences drug response in cancer treatment. We recently reported that FA/BRCA genes are overexpressed and causative for drug resistance in human melphalan-resistant multiple myeloma cell lines. However, the transcriptional regulation of the FA/BRCA pathway is not understood. In this report, we describe for the first time a novel function of the NF-kappa B subunits, RelB/p50, as transcriptional activators of the FA/BRCA pathway. Specifically, our findings point to constitutive phosphorylation Of I kappa B kinase alpha and subsequent alterations in FANCD2 expression and function as underlying events leading to melphalan resistance in repeatedly exposed multiple myeloma cells. Inhibiting NF-kappa B, by small interfering RNA, blocking the I kappa B kinase complex with BMS-345541, or using the proteasome inhibitor bortezomib drastically reduced FA/BRCA gene expression and FANCD2 protein expression in myeloma cells, resulting in diminished DNA damage repair and enhanced melphalan sensitivity. Importantly, we also found that bortezomib decreases FA/BRCA gene expression in multiple myeloma patients. These results show for the first time that NF-kappa B transcriptionally regulates the FA/BRCA pathway and provide evidence for targeting Fanconi anemia-mediated DNA repair to enhance chemotherapeutic response and circumvent drug resistance in myeloma patients. [Cancer Res 2009;69(24):9367-75]