Publication
Title
Hypoxia-induced cisplatin resistance in non-small cell lung cancer cells is mediated by HIF-1 alpha and mutant p53 and can be overcome by induction of oxidative stress
Author
Abstract
The compound APR-246 (PRIMA-1(MET)) is a known reactivator of (mutant) p53 and inducer of oxidative stress which can sensitize cancer cells to platinum-based chemotherapeutics. However, the effect of a hypoxic tumor environment has been largely overlooked in this interaction. This study focusses on the role of hypoxia-inducible factor-1 alpha (HIF-1 alpha) and the p53 tumor suppressor protein in hypoxia-induced cisplatin resistance in non-small cell lung cancer (NSCLC) cells and the potential of APR-246 to overcome this resistance. We observed that hypoxia-induced cisplatin resistance only occurred in the p53 mutant NCI-H2228(Q331)* cell line, and not in the wild type A549 and mutant NCI-H1975(R273H) cell lines. Cisplatin reduced HIF-1 alpha protein levels in NCI-H2228(Q331)* cells, leading to a shift in expression from HIF-1 alpha-dependent to p53-dependent transcription targets under hypoxia. APR-246 was able to overcome hypoxia-induced cisplatin resistance in NCI-H2228(Q331)* cells in a synergistic manner without affecting mutant p53(Q331)* transcriptional activity, but significantly depleting total glutathione levels more efficiently under hypoxic conditions. Synergism was dependent on the presence of mutant p53(Q331)* and the induction of reactive oxygen species, with depletion of one or the other leading to loss of synergism. Our data further support the rationale of combining APR-246 with cisplatin in NSCLC, since their synergistic interaction is retained or enforced under hypoxic conditions in the presence of mutant p53.
Language
English
Source (journal)
Cancers
Publication
2018
ISSN
2072-6694
Volume/pages
10:4(2018), 15 p.
Article Reference
126
ISI
000435179000041
Pubmed ID
29690507
Medium
E-only publicatie
Full text (Publisher's DOI)
Full text (open access)
UAntwerpen
Faculty/Department
Research group
Project info
Preclinical research on the role and mechanism of MDM2 "small molecule" inhibitors combined with conventional chemo- and/or radiotherapy under normoxic and hypoxic conditions.
Targeting polo-like kinase 1 for cancer treatment: focus on combination therapy and the role of the hypoxic microenvironment.
Exploring HIF in poly(I:C)-based immunotherapy to stimulate innate immunity in glioblastoma multiforme.
Involving the innate immune system in p53-targeted combination therapies.
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identification
Creation 10.07.2018
Last edited 17.07.2021
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