title: Hypoxia-induced autophagy as an additional mechanism in human osteosarcoma radioresistance.
abstract: Osteosarcoma (OS) responds poorly to radiotherapy, but the mechanism is unclear. We found OS tumor tissues expressed high level of protein HIF-1α, a common biological marker indicative of hypoxia. It is known that hypoxic cells are generally radioresistant because of reduced production of irradiation-induced DNA-damaging reactive oxygen species (ROS) in the anaerobic condition. Here we report another mechanism how hypoxia induces radioresistance. In MG-63 human osteosarcoma cells, hypoxic pretreatment increased the cellular survival in irradiation. These hypoxia-exposed cells displayed compartmental recruitment of GFP-tagged LC3 and expression of protein LC3-II, and restored the radiosensitivity upon autophagy inhibition. The following immunohistochemistry of OS tumor tissue sections revealed upregulated LC3 expression in a correlation with HIF-1α protein level, implying the possibly causative link between hypoxia and autophagy. Further studies in MG-63 cells demonstrated hypoxic pretreatment reduced cellular and mitochondrial ROS production during irradiation, while inhibition of autophagy re-elicited them. Taken together, our study suggests hypoxia can confer cells resistance to irradiation through activated autophagy to accelerate the clearance of cellular ROS products. This might exist in human osteosarcoma as an additional mechanism for radioresistance.
authors.affiliation: Department of Orthopedics, The Fourth Hospital of Hebei Medical University, 12 Health Road, Shijiazhuang, Hebei 050011, China.
authors.forename: Helin
authors.initials: H
authors.lastname: Feng
authors.affiliation: Department of Orthopedics, The Fourth Hospital of Hebei Medical University, 12 Health Road, Shijiazhuang, Hebei 050011, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Orthopedics, The Third Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang, Hebei 050051, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Cancer Research Institute, The Fourth Hospital of Hebei Medical University, 12 Health Road, Shijiazhuang, Hebei 050011, China.
authors.forename: Baoen
authors.initials: B
authors.lastname: Shan
authors.affiliation: Department of Radiation Oncology, The Fourth Hospital of Hebei Medical University, 12 Health Road, Shijiazhuang, Hebei 050011, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Orthopedics, The Fourth Hospital of Hebei Medical University, 12 Health Road, Shijiazhuang, Hebei 050011, China.
authors.forename: Jianfa
authors.initials: J
authors.lastname: Xu
authors.affiliation: Cancer Research Institute, The Fourth Hospital of Hebei Medical University, 12 Health Road, Shijiazhuang, Hebei 050011, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Orthopedics, The Fourth Hospital of Hebei Medical University, 12 Health Road, Shijiazhuang, Hebei 050011, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Guo
authors.affiliation: Department of Orthopedics, The Third Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang, Hebei 050051, China.
authors.forename: Yingze
authors.initials: Y
authors.lastname: Zhang
keywords: 3-MA, 3-methyladenine; Autophagy; CQ, chloroquine; HIF-1α; HIF-1α, hypoxia-inducible factor 1-alpha; Hypoxia; LC3; LC3, microtubule-associated protein-1 light chain 3; OC, osteochondroma; OS, osteosarcoma; Osteosarcoma; ROS, reactive oxygen species; Radioresistance