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.
Ambiguous roles of genotoxic anticancer therapeutic-induced NF-kappaB 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-kappaB blockage for sensitizing anticancer therapy, we have systematically investigated the effect of distinct NF-kappaB-blocking approaches on lung cancer cells' responses to Adriamycin-induced cytotoxicity. The results show that Adriamycin-induced NF-kappaB activation functions as a transcriptional activator triggering the expression of anti-apoptotic genes. Blocking NF-kappaB with IKKbeta- or RelA siRNA substantially sensitized Adriamycin-induced cytotoxicity, suggesting that the NF-kappaB pathway could be a target for sensitizing lung cancer cells to Adriamycin's anticancer effect. Surprisingly, although it effectively blocks NF-kappaB activation, the IkappaBalpha super-suppressor (IkappaBalphaAA) antagonized Adriamycin-induced cell death. Additionally, the induction of death receptor 5 (DR5), which contributes to Adriamycin-induced cytotoxicity, was not affected by NF-kappaB blockage. Thus, our results suggest that Adriamycin-induced NF-kappaB is a transcriptional activator that protects lung cancer cells against apoptosis, and IKKbeta- or RelA siRNA rather than IkappaBalphaAA is an appropriate NF-kappaB blocking approach for sensitizing lung cancer cells to Adriamycin-induced cytotoxicity.
Chen
Wenshu
W
Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108, USA.
Wang
Xia
X
Bai
Lang
L
Liang
Xiaomin
X
Zhuang
Jianguo
J
Lin
Yong
Y
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology*; D020672:I-kappa B Proteins / Q000235:genetics*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D034741:RNA, Small Interfering / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000235:genetics
D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C498143:RELA protein, human; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D004317:Doxorubicin; D051550:I-kappa B Kinase