Novel mechanism whereby nuclear factor κB mediates DNA damage repair through regulation of O6-methylguanine-DNA-methyltransferase
Novel mechanism whereby nuclear factor κB mediates DNA damage repair through regulation of O6-methylguanine-DNA-methyltransferase
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DOI：
10.1158/0008-5472.can-06-3820
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发表时间：
2007-09-15
期刊：
影响因子：
11.2
通讯作者：
Siegalt, Tali
中科院分区：
文献类型：
--
作者：
Lavon, Iris;Fuchs, Dana;Siegalt, Tali
O-6-甲基鸟嘌呤-DNA-甲基转移酶（MGMT）和核因子κ B（NF-κ B B）是与对基于烷化剂的化疗产生耐药性相关的两个关键效应物。这促使我们推测NF-κ B B可能参与MGMT的调节。与这一假设相一致，我们发现了两个推定的NF-κ B B结合位点内的MGMT启动子区域，并显示了一个特定的和直接的相互作用的NF-κ B在这些网站。在HEK 293细胞中强制表达NF-κ B亚基p65诱导MGMT表达增加，而加入NF-κ B超级阻遏物Delta NI κ B完全消除了诱导作用。我们还发现，在神经胶质瘤细胞系和人类神经胶质瘤中，NF-κ B活化程度与MGMT表达之间存在显著相关性，并表明其独立于MGMT启动子甲基化。我们的研究结果具有潜在的临床意义，因为我们表明具有异位p65或高组成性NF-κ B活性的细胞系对亚硝基脲治疗的敏感性较低，并且用O-6-苄基鸟嘌呤抑制MGMT活性完全消除了NF-κ B获得的化学抗性。我们的研究结果强烈表明，NF-κ B B在MGMT调节中起着重要作用，MGMT很可能是NF-κ B介导的烷化剂耐药性的主要参与者。
O-6-Methylguanine-DNA-methyltransferase (MGMT) and nuclear factor kappa B (NF-kappa B) are two key effectors associated with the development of resistance to alkylating agent-based chemotherapy. This prompted us to hypothesize that NF-kappa B might be involved in MGMT regulation. Consistent with this hypothesis, we have discovered two putative NF-kappa B binding sites within the MGMT promoter region and showed a specific and direct interaction of NF-kappa B at each of these sites. Forced expression of the NF-kappa B subunit p65 in HEK293 cells induced an increase in MGMT expression whereas addition of the NF-kappa B super repressor Delta NI kappa B completely abrogated the induction. We also found a significant correlation between the extent of NF-kappa B activation and MGMT expression in the glioma cell lines and the human glial tumors tested and showed that it was independent of MGMT promoter methylation. Our results are of potential clinical significance because we show that cell lines with ectopic p65 or high constitutive NF-kappa B activity are less sensitive to nitrosourea treatment and that suppression of MGMT activity with O-6-benzylguanine completely abolishes the chemoresistance acquired by NF-kappa B. The findings of our study strongly suggest that NF-kappa B plays a major role in MGMT regulation and that MGMT is most probably the major player in NF-kappa B-mediated chemoresistance to alkylating agents.