Cobalt chloride treatment induces autophagic apoptosis in human glioma cells via a p53-dependent pathway
Journal
International Journal of Oncology
Journal Volume
50
Journal Issue
3
Pages
964-974
Date Issued
2017
Author(s)
Abstract
Malignant glioma is the most aggressive brain tumor. Hypoxic condition has been explored for killing cancer stem cells or drug-resistant tumor cells. This study investigated the effects of hypoxia on autophagic death and the possible mechanisms. Exposure of human malignant glioma U87-MG cells to cobalt chloride (CoCl2) increased cellular hypoxia-inducible factor-1α levels and concurrently decreased cell viability concentration-and time-dependently. In parallel, treatment with CoCl2 suppressed proliferation of human U87-MG cells. Autophagic cells and levels of LC3-II were concentration-and time-dependently induced in human U87-MG cells after exposure to CoCl2. However, pretreatment with 3-mehyladenine (3-MA) and chloroquine, inhibitors of cell autophagy, caused significant alleviations in CoCl2-induced cell autophagy. In contrast, exposure to rapamycin, an inducer of cell autophagy, synergistically induced hypoxiainduced autophagy of U87-MG cells. Administration of human U87-MG cells with CoCl2 triggered caspase-3 activation and cell apoptosis. Interestingly, pretreatment with 3-MA and chloroquine remarkably suppressed CoCl2-induced caspase-3 activation and cell apoptosis. Application of p53 small interference (si)RNA into human U87-MG cells downregulated levels of this protein and simultaneously lowered hypoxiaand 3-MA-induced alterations in cell autophagy, apoptosis, and death. The hypoxia-induced autophagy and apoptosis of DBTRG-05MG cells were significantly lowered by 3-MA pretreatment and p53 knockdown. Therefore, the present study shows that CoCl2 treatment can induce autophagy of human glioma cells and subsequent autophagic apoptosis via a p53-dependent pathway. Hypoxia-induced autophagic apoptosis may be applied as a therapeutic strategy for treatment of glioma patients.
Subjects
Autophagic Apoptosis; Autophagy; Hypoxia; Malignant Glioma; P53
SDGs
Other Subjects
caspase 3; cobalt chloride; hypoxia inducible factor 1alpha; protein p53; 3-methyladenine; adenine; antimutagenic agent; caspase 3; chloroquine; cobalt; cobalt chloride; HIF1A protein, human; hypoxia inducible factor 1alpha; MAP1LC3A protein, human; microtubule associated protein; protein p53; rapamycin; reactive oxygen metabolite; small interfering RNA; TP53 protein, human; antineoplastic activity; antiproliferative activity; apoptosis; Article; autophagy; cell hypoxia; cell survival; cell viability; concentration response; controlled study; down regulation; drug cytotoxicity; drug mechanism; enzyme activation; glioma cell; human; human cell; analogs and derivatives; apoptosis; autophagy; Brain Neoplasms; cell proliferation; drug effects; genetics; glioma; metabolism; pathology; RNA interference; tumor cell line; Adenine; Antimutagenic Agents; Apoptosis; Autophagy; Brain Neoplasms; Caspase 3; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chloroquine; Cobalt; Glioma; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Microtubule-Associated Proteins; Reactive Oxygen Species; RNA Interference; RNA, Small Interfering; Sirolimus; Tumor Suppressor Protein p53
Publisher
Spandidos Publications
Type
journal article