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Title
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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
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Author
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Abstract
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| 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. |
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Language
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English
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Source (journal)
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Cancers
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Publication
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2018
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ISSN
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2072-6694
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Volume/pages
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10
:4
(2018)
, 15 p.
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Article Reference
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126
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ISI
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000435179000041
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Pubmed ID
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29690507
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Medium
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E-only publicatie
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Full text (Publisher's DOI)
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Full text (open access)
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