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Hypoxia Induced by Cobalt Chloride Triggers Autophagic Apoptosis of Human and Mouse Drug-Resistant Glioblastoma Cells through Targeting the PI3K-AKT-mTOR Signaling Pathway.
- Source :
-
Oxidative medicine and cellular longevity [Oxid Med Cell Longev] 2021 May 27; Vol. 2021, pp. 5558618. Date of Electronic Publication: 2021 May 27 (Print Publication: 2021). - Publication Year :
- 2021
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Abstract
- Glioblastoma multiforme (GBM) is the most aggressive brain tumor. Drug resistance mainly drives GBM patients to poor prognoses because drug-resistant glioblastoma cells highly defend against apoptotic insults. This study was designed to evaluate the effects of cobalt chloride (CoCl <subscript>2</subscript> ) on hypoxic stress, autophagy, and resulting apoptosis of human and mouse drug-resistant glioblastoma cells. Treatment of drug-resistant glioblastoma cells with CoCl <subscript>2</subscript> increased levels of hypoxia-inducible factor- (HIF-) 1 α and triggered hypoxic stress. In parallel, the CoCl <subscript>2</subscript> -induced hypoxia decreased mitochondrial ATP synthesis, cell proliferation, and survival in chemoresistant glioblastoma cells. Interestingly, CoCl <subscript>2</subscript> elevated the ratio of light chain (LC)3-II over LC3-I in TMZ-resistant glioblastoma cells and subsequently induced cell autophagy. Analyses by loss- and gain-of-function strategies further confirmed the effects of the CoCl <subscript>2</subscript> -induced hypoxia on autophagy of drug-resistant glioblastoma cells. Furthermore, knocking down HIF-1 α concurrently lessened CoCl <subscript>2</subscript> -induced cell autophagy. As to the mechanisms, the CoCl <subscript>2</subscript> -induced hypoxia decreased levels of phosphoinositide 3-kinase (PI3K) and successive phosphorylations of AKT and mammalian target of rapamycin (mTOR) in TMZ-resistant glioblastoma cells. Interestingly, long-term exposure of human chemoresistant glioblastoma cells to CoCl <subscript>2</subscript> sequentially triggered activation of caspases-3 and -6, DNA fragmentation, and cell apoptosis. However, pretreatment with 3-methyladenine, an inhibitor of autophagy, significantly attenuated the CoCl <subscript>2</subscript> -induced autophagy and subsequent apoptotic insults. Taken together, this study showed that long-term treatment with CoCl <subscript>2</subscript> can induce hypoxia and subsequent autophagic apoptosis of drug-resistant glioblastoma cells via targeting the PI3K-AKT-mTOR pathway. Thus, combined with traditional prescriptions, CoCl <subscript>2</subscript> -induced autophagic apoptosis can be clinically applied as a de novo strategy for therapy of drug-resistant GBM patients.<br />Competing Interests: The authors declare that there is no conflict of interest.<br /> (Copyright © 2021 Yuan-Wen Lee et al.)
- Subjects :
- Animals
Apoptosis
Brain Neoplasms pathology
Cell Line, Tumor
Cell Proliferation
Glioblastoma pathology
Humans
Mice
Signal Transduction
Brain Neoplasms complications
Cell Hypoxia genetics
Cobalt adverse effects
Glioblastoma complications
Phosphatidylinositol 3-Kinase metabolism
Phosphatidylinositol 3-Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1942-0994
- Volume :
- 2021
- Database :
- MEDLINE
- Journal :
- Oxidative medicine and cellular longevity
- Publication Type :
- Academic Journal
- Accession number :
- 34136065
- Full Text :
- https://doi.org/10.1155/2021/5558618