|Reference : Differential effects of hypoxia on etoposide-induced apoptosis according to the cance...|
|Scientific journals : Article|
|Human health sciences : Oncology|
|Differential effects of hypoxia on etoposide-induced apoptosis according to the cancer cell lines|
|Cosse, Jean-Philippe [Université de Liège - ULg > > GIGA-R : Epigénétique Cellulaire et Moléculaire >]|
|Sermeus, Audrey [ > > ]|
|Vannuvel, Kayleen [ > > ]|
|Ninane, Noelle [ > > ]|
|Raes, Martine [ > > ]|
|Michiels, Carine [ > > ]|
|Yes (verified by ORBi)|
|[en] Hypoxia ; apoptosis ; etoposide|
|[en] Background: It is more and more recognized that hypoxia plays a role in the resistance of cancer
cells to chemotherapy. However, the mechanisms underlying this resistance still need deeper
understanding. The aim of this study was to investigate the effect of hypoxia on this process since
hypoxia is one of the hallmarks of tumor environment.
Results: The effect of hypoxia on the apoptosis induced by etoposide, one drug commonly used
in chemotherapy, was investigated using three different cancer cell lines. Gene expression changes
were also studied in order to delineate the mechanisms responsible for the hypoxia-induced
chemoresistance. We observed that hypoxia differentially influenced etoposide-induced cell death
according to the cancer cell type. While hypoxia inhibited apoptosis in hepatoma HepG2 cells, it
had no influence in lung carcinoma A549 cells and further enhanced it in breast cancer MCF-7 cells.
Etoposide increased p53 activity in all cell lines while hypoxia alone decreased it only in HepG2
cells. Hypoxia had no influence on the etoposide-induced p53 activity in A549, increased p53
abundance in MCF-7 cells but markedly decreased p53 activity in HepG2 cells. Using low density
DNA arrays to detect the expression of genes involved in the regulation of apoptosis, etoposide
and hypoxia were shown to each influence the expression of numerous genes, many of the ones
influenced by etoposide being p53 target genes. Again, the influence of hypoxia on the etoposideinduced
changes was different according to the cell type.
Conclusion: These results evidenced that there was a striking parallelism between the effect of
hypoxia on the etoposide-induced p53 stabilization as well as p53 target gene expression and its
effect on the etoposide-induced apoptosis according to the cell type. They are very interesting not
only because they provide one possible mechanism for the induction of chemoresistance under
hypoxic conditions in cells like HepG2 but also because they indicate that not all cell types respond
the same way. This knowledge is of importance in designing adequate treatment according to the
type of tumors.
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