title: Mutations of p53 and KRAS activate NF-κB to promote chemoresistance and tumorigenesis via dysregulation of cell cycle and suppression of apoptosis in lung cancer cells.
abstract: Although mutations of p53 and KRAS and activation of NF-κB signaling have been highly associated with chemoresistance and tumorigenesis of lung cancer, the interactive mechanisms between two of p53, KRAS, and NF-κB are elusive. In the present study, we first observed that blocking of NF-κB function in KRAS mutant A549 cell line with an IκBα mutant (IκBαM) inhibited cell cycle progression, anti-apoptosis, chemoresistance, and tumorigenesis. Silencing of p53 or KRAS in A549 or H358 cells either enhanced or attenuated the resistance of cells to cisplatin and taxol through promotion or suppression of the NF-κB p65 nuclear translocation. Introduction of a wild type p53 into p53 null lung cancer cell lines H1299 and H358 inhibited NF-κB activity, leading to the enhanced response to chemotherapeutic drugs. Delivery of a mutant p53 or KRAS-V12 into A549/IκBαM or H1299/p53Wt cells increased cell cycle progression, anti-apoptosis, chemoresistance, and tumorigenesis due to the accumulated nuclear localization of NF-κB p65, while treatment of H1299/p53Wt/KRAS-V12 with NF-κB inhibitor PS1145 diminished these effects. Thus, we conclude that p53 deficiency and KRAS mutation activate the NF-κB signaling to control chemoresistance and tumorigenesis, and that the status of p53 and KRAS may be considered for the targeted therapy against NF-κB in lung cancer patients.
authors.affiliation: Central Laboratory, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China; Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Fudan University Shanghai Medical College, Shanghai, 200032, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Yang
authors.affiliation: Central Laboratory, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China.
authors.forename: Yunjiao
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Central Laboratory, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Li
authors.affiliation: Central Laboratory, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Central Laboratory, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China.
authors.forename: Yougen
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Central Laboratory, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China.
authors.forename: Yunqing
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Central Laboratory, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China; Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Fudan University Shanghai Medical College, Shanghai, 200032, China. Electronic address: yanggong@fudan.edu.cn.
authors.forename: Gong
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Osteology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China. Electronic address: hongyangcm@163.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Hong
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D015153:Blotting, Western; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D011725:Pyridines / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; C117307:KRAS protein, human; D016328:NF-kappa B; C456319:PS1145; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D051550:I-kappa B Kinase; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D017239:Paclitaxel; D002945:Cisplatin
keywords: Chemoresistance; KRAS; Lung cancer; NF-κB; p53