Hyperoxia sensitizes hypoxic HeLa cells to ionizing radiation by downregulating HIF-1α and VEGF expression

The current study investigated whether hyperoxia may reverse hypoxia-induced radioresistance (RR) in cervical cancer. Human HeLa cells exposed to hypoxic, normoxic or hyperoxic conditions were irradiated using X-rays. Cell proliferation and apoptosis were analyzed using MTT assays and flow cytometry. The expression levels of hypoxia-inducible factor-1α (HIF-1α), VEGF(165), VEGFRs, Akt and ERK were measured via western blotting and/or ELISA. The results demonstrated that hypoxia stimulated HIF-1α and VEGF expression, and induced RR in HeLa cells. The administration of recombinant VEGF or the forced expression of VEGF promoted RR, whereas inactivating HIF-1α or blocking the VEGF-VEGFR interaction abrogated hypoxia-induced RR. Notably, hyperoxia decreased the level of hypoxia-stimulated HIF-1α and VEGF, and enhanced radiosensitivity in hypoxic HeLa cells. The results demonstrated that hyperoxia suppressed the hypoxia-activated Akt and ERK signaling pathways in HeLa cells. Therefore, a high O(2) concentration may be considered as a radiotherapeutic sensitizer for hypoxic HeLa cells.