Anti-apoptotic role of HIF-1 and AP-1 in paclitaxel exposed breast cancer cells under hypoxia.
BACKGROUND
Hypoxia is a hallmark of solid tumors and is associated with metastases, therapeutic resistance and poor patient survival.


RESULTS
In this study, we showed that hypoxia protected MDA-MB-231 breast cancer cells against paclitaxel- but not epirubicin-induced apoptosis. The possible implication of HIF-1 and AP-1 in the hypoxia-induced anti-apoptotic pathway was investigated by the use of specific siRNA. Specific inhibition of the expression of these two transcription factors was shown to increase apoptosis induced by chemotherapeutic agents under hypoxia indicating an involvement of HIF-1 and AP-1 in the anti-apoptotic effect of hypoxia. After HIF-1 specific inhibition and using TaqMan Human Apoptosis Array, 8 potential HIF-1 target genes were identified which could take part in this protection. Furthermore, Mcl-1 was shown to be a potential AP-1 target gene which could also participate to the hypoxia-induced chemoresistance.


CONCLUSIONS
Altogether, these data highlight two mechanisms by which hypoxia could mediate its protective role via the activation of two transcription factors and, consecutively, changes in gene expression encoding different anti- and pro-apoptotic proteins.
Flamant
Lionel
L
Laboratory of Biochemistry and cellular Biology (URBC), NARILIS - NAmur Research Institute for LIfe Sciences - FUNDP-University of Namur, 5000 Namur, Belgium.
Notte
Annick
A
Ninane
Noelle
N
Raes
Martine
M
Michiels
Carine
C
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D017239:Paclitaxel / Q000494:pharmacology*; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1 / Q000502:physiology*
D000972:Antineoplastic Agents, Phytogenic; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D017239:Paclitaxel