Molecular radiobiologyPhosphorylation of eIF2α is required for mRNA translation inhibition and survival during moderate hypoxia
Section snippets
Cell models
Our studies included the following human cell lines: HeLa (cervix carcinoma), DU145 (prostate carcinoma derived from brain metastasis), HT-29 (colorectal adenocarcinoma), MCF7 (mammary adenocarcinoma derived from pleural effusion), U373 MG (glioblastoma–astrocytoma), BJ-hTERT (normal skin fibroblasts transformed with human telomerase). Mouse embryo fibroblasts (MEF) wild-type (wt) or with a knock-in mutation for eIF2α (S51A) were transformed with SV40 Large T antigen and previously described
Results
We have previously shown that acute exposure to anoxia severely inhibits mRNA translation in HeLa cells [9]. However, since tumor cells are known to be exposed to a wide range of oxygen tensions, we investigated whether this inhibition also occurred at higher oxygen concentrations. To this end, we exposed HeLa cells to 0.0%, 0.2% and 2.0% oxygen and quantified global mRNA translation efficiency using the polysome assay. In this assay, RNA complexes are separated by centrifugation through a
Discussion
It can be argued that the molecular pathways which are activated early in response to hypoxia may be most attractive to target because they potentially affect all hypoxic cells. The data presented here show that a large panel of cells, including normal cells as well as metastatic breast and prostate cancer cells, inhibit mRNA translation to a very similar extent in response to acute hypoxia or anoxia. The molecular pathways that regulate translation during acute hypoxia do not appear to be
Acknowledgements
We acknowledge financial support from the Dutch Science Organization (ZonMW-NWO Top Grant 912-03-047 to BW, and ZonMW-VENI Grant 016.056.015 to MK), the Dutch Cancer Society (KWF Grant UM 2003-2821 to BW), and the EU 6th framework program (Euroxy program to BW).
The technical assistance of Mieke Duysinx is highly appreciated.
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