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

• Published in: Cancer letters 2015-02, Vol.357 (2), p.520-526
• Main Authors: Yang, Lina, Zhou, Yunjiao, Li, Yinghua, Zhou, Juan, Wu, Yougen, Cui, Yunqing, Yang, Gong, Hong, Yang
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus - drug effects; Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis - genetics; Blotting, Western; Carcinogenesis - drug effects; Carcinogenesis - genetics; Cell Cycle - drug effects; Cell Cycle - genetics; Cell Line, Tumor; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Chemoresistance; Cisplatin - pharmacology; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Hematology, Oncology and Palliative Medicine; Heterocyclic Compounds, 3-Ring - pharmacology; Humans; I-kappa B Kinase - antagonists & inhibitors; I-kappa B Kinase - metabolism; KRAS; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Mice, Inbred BALB C; Mutation; NF-kappa B - metabolism; NF-κB; p53; Paclitaxel - pharmacology; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins p21(ras); Pyridines - pharmacology; ras Proteins - genetics; ras Proteins - metabolism; Transcription Factor RelA - metabolism; Tumor Burden - drug effects; Tumor Burden - genetics; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Xenograft Model Antitumor Assays - methods
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2014.12.003

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.