Cobalt chloride treatment induces autophagic apoptosis in human glioma cells via a p53-dependent pathway

Cheng,Bor-Chin; Chen,Jui-Tai; Yang,Shun-Tai; Chio,Chung-Ching; Liu,Shing-Hwa; Chen,Ruei-Ming

doi:10.3892/ijo.2017.3861

Cobalt chloride treatment induces autophagic apoptosis in human glioma cells via a p53-dependent pathway

Authors:
- Bor-Chin Cheng
- Jui-Tai Chen
- Shun-Tai Yang
- Chung-Ching Chio
- Shing-Hwa Liu
- Ruei-Ming Chen
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Affiliations: Department of Surgery, Chi-Mei Medical Center, Tainan, Taiwan, R.O.C., Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan, R.O.C., Department of Neurosurgery, Shuang-Ho Hospital, Taipei Medical University, New Taipei City, Taiwan, R.O.C., Department of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan, R.O.C., Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan, R.O.C., Comprehensive Cancer Center, Taipei Medical University, Taipei, Taiwan, R.O.C.
Published online on: January 25, 2017 https://doi.org/10.3892/ijo.2017.3861
Pages: 964-974

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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 hypoxia-induced 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 hypoxia- and 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.

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