Blockage of NF-kappaB by IKKbeta- or RelA-siRNA rather than the NF-kappaB super-suppressor IkappaBalpha mutant potentiates adriamycin-induced cytotoxicity in lung cancer cells.
Blockage of NF-kappaB by IKKbeta- or RelA-siRNA rather than the NF-kappaB super-suppressor IkappaBalpha mutant potentiates adriamycin-induced cytotoxicity in lung cancer cells.
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DOI：
10.1002/jcb.21856
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发表时间：
2008-10-01
影响因子：
4
通讯作者：
Lin, Yong
中科院分区：
文献类型：
--
作者：
Chen, Wenshu;Wang, Xia;Bai, Lang;Liang, Xiaomin;Zhuang, Jianguo;Lin, Yong
最近提出了基因毒性抗癌治疗诱导的NF-κB活化在调节基因表达（活化或抑制）和细胞凋亡（抗或促细胞凋亡）中的双重作用。为了澄清这一争议并确定NF-κB阻断对增敏抗癌治疗的有用性，我们系统地研究了不同的NF-κ B阻断方法对肺癌细胞对阿霉素诱导的细胞毒性反应的影响。结果表明，阿霉素诱导的NF-κB活化作为转录激活因子触发抗凋亡基因的表达。用IKKβ或RelA siRNA阻断NF-κB可显著敏化阿霉素诱导的细胞毒性，表明NF-κB通路可能是使肺癌细胞对阿霉素的抗癌作用敏感的靶点。令人惊讶的是，尽管I κ B α能有效阻断NF-κB的活化，但IκBα超抑制因子（IκBαAA）能拮抗阿霉素诱导的细胞死亡。此外，诱导死亡受体5（DR 5），这有助于阿霉素诱导的细胞毒性，不受NF-κB阻断。因此，我们的研究结果表明，阿霉素诱导的NF-κB是一种转录激活因子，可保护肺癌细胞免于凋亡，IKKβ或RelA siRNA而不是IκBαAA是一种合适的NF-κB阻断方法，可使肺癌细胞对阿霉素诱导的细胞毒性敏感。
Ambiguous roles of genotoxic anticancer therapeutic-induced NF-κB activation in regulating gene expression (activation or suppression) and apoptosis (anti- or pro-apoptosis) have recently been suggested. In order to clarify this controversy and determine the usefulness of NF-κB blockage for sensitizing anticancer therapy, we have systematically investigated the effect of distinct NF-κB-blocking approaches on lung cancer cells’ responses to Adriamycin-induced cytotoxicity. The results show that Adriamycin-induced NF-κB activation functions as a transcriptional activator triggering the expression of anti-apoptotic genes. Blocking NF-κB with IKKβ or RelA siRNA substantially sensitized Adriamycin-induced cytotoxicity, suggesting that the NF-κB pathway could be a target for sensitizing lung cancer cells to Adriamycin’s anticancer effect. Surprisingly, although it effectively blocks NF-κB activation, the IκBα super-suppressor (IκBαAA) antagonized Adriamycin-induced cell death. Additionally, the induction of death receptor 5 (DR5), which contributes to Adriamycin-induced cytotoxicity, was not affected by NF-κB blockage. Thus, our results suggest that Adriamycin-induced NF-κB is a transcriptional activator that protects lung cancer cells against apoptosis, and IKKβ or RelA siRNA rather than IκBαAA is an appropriate NF-κB blocking approach for sensitizing lung cancer cells to Adriamycin-induced cytotoxicity.
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