Hyperoxia sensitizes hypoxic HeLa cells to ionizing radiation by downregulating HIF‑1α and VEGF expression
Dan Dong, Yan Fu, Feng Chen, Jing Zhang, Haiyan Jia, Jia Li, Huailin Wang, Jihong Wen
Abstract
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<sub>165</sub>, 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<sub>2</sub> concentration may be considered as a radiotherapeutic sensitizer for hypoxic HeLa cells.