[en] Tumor hypoxia is one of the features of tumor microenvironment that contributes to chemoresistance in particular
by cellular adaptations that modulate the apoptotic process. However, the mechanisms involved in this resistance
still need deeper understanding. In this study, we investigated the involvement of four transcription factors, c-Myc,
nuclear factor κB (NF-κB), p53, and c-jun/activator protein 1 (AP-1) in the hypoxia-induced resistance to etoposide in
HepG2 cells. Whereas the profile of c-Myc and NF-κB activity did not fit the effect of hypoxia on caspase 3 activity,
hypoxia decreased basal p53 abundance and DNA binding activity as well as p53 etoposide-induced activation.
Short interfering RNA (siRNA) silencing evidenced that p53 was required for etoposide-induced apoptosis under
normoxia. An inhibition of its activity under hypoxia could thus be responsible at least in part for the protection
observed under hypoxic conditions. Moreover, p53 was found to induce the expression of Bak1. We showed that
Bak1 was involved in the etoposide-induced apoptosis because Bak1 siRNA decreased it. Conversely, hypoxia
increased c-jun DNA binding activity in the presence of etoposide. siRNA-mediated silencing of c-jun increased the
responsiveness of cells to etoposide under hypoxia, as shown by an increase in caspase 3 activity and lactate
dehydrogenase release. These effects occurred in a p53-independent manner. These data evidenced that hypoxia
decreased the responsiveness of HepG2 cells to etoposide at least by two independent pathways involving p53
inhibition and c-jun activation.
Research center :
Unité de Recherche en Biologie Cellulaire
Disciplines :
Oncology
Author, co-author :
Cosse, Jean-Philippe ; Université de Liège - ULiège > GIGA-R : Epigénétique Cellulaire et Moléculaire
Ronvaux, Marie
Ninane, Noelle
Raes, Martine
Michiels, Carine
Language :
English
Title :
Hypoxia-Induced Decrease in p53 Protein Level and Increase in c-jun DNA Binding Activity Results in Cancer Cell Resistance to Etoposide
Publication date :
October 2009
Journal title :
Neoplasia
ISSN :
1522-8002
eISSN :
1476-5586
Publisher :
BC Decker, Hamilton Ont, Canada
Volume :
11
Pages :
976-986
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
FUNDP - Facultés Universitaires Notre-Dame de la Paix [BE]
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