Reference : Hypoxia induces protection against etoposide-induced apoptosis: molecular profiling of c...
Scientific journals : Article
Human health sciences : Oncology
http://hdl.handle.net/2268/84918
Hypoxia induces protection against etoposide-induced apoptosis: molecular profiling of changes in gene expression and transcription factor activity
English
Sermeus, Audrey [ > > ]
Cosse, Jean-Philippe mailto [Université de Liège - ULg > > GIGA-R : Epigénétique Cellulaire et Moléculaire >]
Crespin, Marianne [ > > ]
Mainfroid, Véronique [ > > ]
de Longueville, Françoise [ > > ]
Ninane, Noelle [ > > ]
Raes, Martine [ > > ]
Remacle, Jose [ > > ]
Michiels, Carine [ > > ]
2008
Molecular Cancer
7
27
Yes (verified by ORBi)
International
1476-4598
[en] Hypoxia ; Etoposide ; Apoptosis
[en] Background: it is now well established that hypoxia renders tumor cells resistant to radio- but
also chemotherapy. However, few elements are currently available as for the mechanisms
underlying this protection.
Results: in this study, physiological hypoxia was shown to inhibit apoptosis induced in HepG2 cells
by etoposide. Indeed, hypoxia reduced DNA fragmentation, caspase activation and PARP cleavage.
The DNA binding activity of 10 transcription factors was followed while the actual transcriptional
activity was measured using specific reporter plasmids. Of note is the inhibition of the etoposideinduced
activation of p53 under hypoxia. In parallel, data from low density DNA microarrays
indicate that the expression of several pro- and anti-apoptotic genes was modified, among which
are Bax and Bak whose expression profile paralleled p53 activity. Cluster analysis of data unravels
several possible pathways involved in the hypoxia-induced protection against etoposide-induced
apoptosis: one of them could be the inhibition of p53 activity under hypoxia since caspase 3 activity
parallels Bax and Bak expression profile. Moreover, specific downregulation of HIF-1α by RNA
interference significantly enhanced apoptosis under hypoxia possibly by preventing the hypoxia
mediated decrease in Bak expression without altering Bax expression.
Conclusion: these results are a clear demonstration that hypoxia has a direct protective effect on
apoptotic cell death. Moreover, molecular profiling points to putative pathways responsible for
tumor growth in challenging environmental conditions and cancer cell resistance to
chemotherapeutic agents.
Unité de Recherche en Biologie Cellulaire
Facultés Universitaires Notre-Dame de La Paix
Researchers
http://hdl.handle.net/2268/84918
10.1186/1476-4598-7-27

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