Journal
CANCER LETTERS
Volume 357, Issue 2, Pages 520-526Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2014.12.003
Keywords
p53; KRAS; NF-kappa B; Chemoresistance; Lung cancer
Categories
Funding
- National Natural Science Foundation of China [81171911, 81372797, 91129721]
- Shanghai Municipal Health Bureau [20114009]
- Ministry of Education of China [20120071110079]
Ask authors/readers for more resources
Although mutations of p53 and KRAS and activation of NF-kappa B signaling have been highly associated with chemoresistance and tumorigenesis of lung cancer, the interactive mechanisms between two of p53, KRAS, and NF-kappa B are elusive. In the present study, we first observed that blocking of NF-kappa B function in KRAS mutant A549 cell line with an I kappa B alpha mutant (I kappa B alpha M) 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-kappa B p65 nuclear translocation. Introduction of a wild type p53 into p53 null lung cancer cell lines H1299 and H358 inhibited NF-kappa B activity, leading to the enhanced response to chemotherapeutic drugs. Delivery of a mutant p53 or KRAS-V12 into A549/I kappa B alpha M or H1299/p53Wt cells increased cell cycle progression, anti-apoptosis, chemoresistance, and tumorigenesis due to the accumulated nuclear localization of NF-kappa B p65, while treatment of H1299/p53Wt/KRAS-V12 with NF-kappa B inhibitor PSI 145 diminished these effects. Thus, we conclude that p53 deficiency and KRAS mutation activate the NF-kappa B signaling to control chemoresistance and tumorigenesis, and that the status of p53 and KRAS may be considered for the targeted therapy against NF-kappa B in lung cancer patients. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available