Yuhong Zhang1, Xinglong Liu1, Liang Zeng1, Xinrui Zhao1, Qianping Chen1, Yan Pan1, Yang Bai1, Chunlin Shao2, Jianghong Zhang3. 1. Institute of Radiation Medicine, Shanghai Medical College, Fudan University, 200032, Shanghai, China. 2. Institute of Radiation Medicine, Shanghai Medical College, Fudan University, 200032, Shanghai, China. clshao@shmu.edu.cn. 3. Institute of Radiation Medicine, Shanghai Medical College, Fudan University, 200032, Shanghai, China. zjh551268@fudan.edu.cn.
Abstract
BACKGROUND: Hypoxia-mediated radioresistance is a major reason for the adverse radiotherapy outcome of non-small cell lung cancer (NSCLC) in clinical, but the underlying molecular mechanisms are still obscure. METHODS: Cellular and exosomal ANGPTL4 proteins under different oxygen status were examined. Colony survival, lipid peroxidation and hallmark proteins were employed to determine the correlation between ferroptosis and radioresistance. Gene regulations, western blot and xenograft models were used to explore the underlying mechanisms of the role of ANGPTL4 in radioresistance. RESULTS: ANGPTL4 had a much higher level in hypoxic NSCLC cells compared to normoxic cells. Up- or down- regulation of ANGPTL4 positively interrelated to the radioresistance of NSCLC cells and xenograft tumours. GPX4-elicited ferroptosis suppression and lipid peroxidation decrease were authenticated to be involved in the hypoxia-induced radioresistance. ANGPTL4 encapsulated in the exosomes from hypoxic cells was absorbed by neighbouring normoxic cells, resulting in radioresistance of these bystander cells in a GPX4-dependent manner, which was diminished when ANGPTL4 was downregulated in the donor exosomes. CONCLUSION: Hypoxia-induced ANGPTL4 rendered radioresistance of NSCLC through at least two parallel pathways of intracellular ANGPTL4 and exosomal ANGPTL4, suggesting that ANGPTL4 might applicable as a therapeutic target to improve the therapeutic efficacy of NSCLC.
BACKGROUND: Hypoxia-mediated radioresistance is a major reason for the adverse radiotherapy outcome of non-small cell lung cancer (NSCLC) in clinical, but the underlying molecular mechanisms are still obscure. METHODS: Cellular and exosomal ANGPTL4 proteins under different oxygen status were examined. Colony survival, lipid peroxidation and hallmark proteins were employed to determine the correlation between ferroptosis and radioresistance. Gene regulations, western blot and xenograft models were used to explore the underlying mechanisms of the role of ANGPTL4 in radioresistance. RESULTS: ANGPTL4 had a much higher level in hypoxic NSCLC cells compared to normoxic cells. Up- or down- regulation of ANGPTL4 positively interrelated to the radioresistance of NSCLC cells and xenograft tumours. GPX4-elicited ferroptosis suppression and lipid peroxidation decrease were authenticated to be involved in the hypoxia-induced radioresistance. ANGPTL4 encapsulated in the exosomes from hypoxic cells was absorbed by neighbouring normoxic cells, resulting in radioresistance of these bystander cells in a GPX4-dependent manner, which was diminished when ANGPTL4 was downregulated in the donor exosomes. CONCLUSION: Hypoxia-induced ANGPTL4 rendered radioresistance of NSCLC through at least two parallel pathways of intracellular ANGPTL4 and exosomal ANGPTL4, suggesting that ANGPTL4 might applicable as a therapeutic target to improve the therapeutic efficacy of NSCLC.
Authors: Michael S Binkley; Young-Jun Jeon; Monica Nesselbush; Everett J Moding; Barzin Y Nabet; Diego Almanza; Christian Kunder; Henning Stehr; Christopher H Yoo; Siyeon Rhee; Michael Xiang; Jacob J Chabon; Emily Hamilton; David M Kurtz; Linda Gojenola; Susie Grant Owen; Ryan B Ko; June Ho Shin; Peter G Maxim; Natalie S Lui; Leah M Backhus; Mark F Berry; Joseph B Shrager; Kavitha J Ramchandran; Sukhmani K Padda; Millie Das; Joel W Neal; Heather A Wakelee; Ash A Alizadeh; Billy W Loo; Maximilian Diehn Journal: Cancer Discov Date: 2020-10-18 Impact factor: 38.272