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Cancers (Basel). 2018 Apr 21;10(4). pii: E126. doi: 10.3390/cancers10040126.

Hypoxia-Induced Cisplatin Resistance in Non-Small Cell Lung Cancer Cells Is Mediated by HIF-1α and Mutant p53 and Can Be Overcome by Induction of Oxidative Stress.

Author information

1
Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. christophe.deben@uantwerpen.be.
2
Department of Pathology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Antwerp, Belgium. christophe.deben@uantwerpen.be.
3
Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. vanessa.deschoolmeester@uantwerpen.be.
4
Department of Pathology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Antwerp, Belgium. vanessa.deschoolmeester@uantwerpen.be.
5
Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. jorrit.dewaele@uantwerpen.be.
6
Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. julie.jacobs@uantwerpen.be.
7
Department of Pathology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Antwerp, Belgium. julie.jacobs@uantwerpen.be.
8
Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. jolien.vandenbossche@uantwerpen.be.
9
Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. an.wouters@uantwerpen.be.
10
Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. marc.peeters@uza.be.
11
Department of Medical Oncology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Antwerp, Belgium. marc.peeters@uza.be.
12
Department of Medical Oncology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Antwerp, Belgium. christian.rolfo@uza.be.
13
Phase-1 Early Clinical Trials Unit, Antwerp University Hospital, Wilrijkstraat 10, 2650 Antwerp, Belgium. christian.rolfo@uza.be.
14
Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. evelien.smits@uantwerpen.be.
15
Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. filip.lardon@uantwerpen.be.
16
Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Patrick.pauwels@uza.be.
17
Department of Pathology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Antwerp, Belgium. Patrick.pauwels@uza.be.

Abstract

The compound APR-246 (PRIMA-1MET) 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-1α (HIF-1α) 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-H2228Q331* cell line, and not in the wild type A549 and mutant NCI-H1975R273H cell lines. Cisplatin reduced HIF-1α protein levels in NCI-H2228Q331* cells, leading to a shift in expression from HIF-1α-dependent to p53-dependent transcription targets under hypoxia. APR-246 was able to overcome hypoxia-induced cisplatin resistance in NCI-H2228Q331* cells in a synergistic manner without affecting mutant p53Q331* transcriptional activity, but significantly depleting total glutathione levels more efficiently under hypoxic conditions. Synergism was dependent on the presence of mutant p53Q331* 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.

KEYWORDS:

HIF-1α; NSCLC; cisplatin resistance; hypoxia; p53

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