Hypoxia induces sorafenib resistance mediated by autophagy via activating FOXO3a in hepatocellular carcinoma

Autor: Zhebin Dong, Hong Li, Weiming Yu, Jie Shen, Xianlei Cai, Wei Chen, Miaozun Zhang, Chao Liang, Yuan Xu
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Sorafenib
Cancer microenvironment
Cancer Research
Carcinoma
Hepatocellular
Transcriptional factor
Immunology
Antineoplastic Agents
urologic and male genital diseases
Transfection
Article
Dephosphorylation
03 medical and health sciences
Cellular and Molecular Neuroscience
Mice
0302 clinical medicine
Autophagy
Tumor Microenvironment
Medicine
Chemotherapy
Animals
Humans
heterocyclic compounds
Cytotoxicity
neoplasms
business.industry
Forkhead Box Protein O3
Liver Neoplasms
Cell Biology
Hypoxia (medical)
medicine.disease
female genital diseases and pregnancy complications
digestive system diseases
Cell Hypoxia
Sorafenib resistance
Cancer therapeutic resistance
030104 developmental biology
030220 oncology & carcinogenesis
Hepatocellular carcinoma
Cancer research
medicine.symptom
business
medicine.drug
Zdroj: Cell Death & Disease
ISSN: 2041-4889
Popis: Sorafenib, a multikinase inhibitor, is considered as the only approved drug to cure the advanced hepatocellular carcinoma (HCC); however, the acquired chemoresistance caused by intratumoral hypoxia through sorafenib long term therapy induces sorafenib inefficacy. We demonstrated here that hypoxia significantly attenuated sensitivity of HCC cells to sorafenib treatment and reduced its proliferation. Autophagy was observed in sorafenib-treated HCC cells in hypoxia, and inhibition of autophagy by 3-MA eliminated hypoxia-induced sorafenib resistance. Further study revealed hypoxia-activated FOXO3a, an important cellular stress transcriptional factor, via inducing its dephosphorylation and nuclear location; and FOXO3a-dependent transcriptive activation of beclin-1 was responsible for hypoxia-induced autophagy in HCC cells. Knockout of FOXO3a inhibited the autophagy induced by sorafenib itself in normoxia and significantly enhanced the cytotoxicity of sorafenib in HCC cells; and it also inhibited the hypoxia-induced autophagy and achieved the same effect in sorafenib sensitivity-enhancement in HCC cells as it in normoxia. Finally, knockout of intratumoral FOXO3a significantly enhanced curative efficacy of sorafenib via inhibition of autophagy in xenograft tumors in nude mice. Collectively, our study suggests that FOXO3a plays a key role in regulating hypoxia-induced autophagy in sorafenib-treated HCC, and FOXO3-targeted therapy may serve as a promising approach to improve clinical prognosis of patients suffering from HCC.
Databáze: OpenAIRE
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