Autophagy inhibitors regulate TRAIL sensitivity in human malignant cells by targeting the mitochondrial network and calcium dynamics.
Int J Oncol
; 54(5): 1734-1746, 2019 May.
Article
em En
| MEDLINE
| ID: mdl-30896851
ABSTRACT
In a variety of cancer cell types, the pharmacological and genetic blockade of autophagy increases apoptosis induced by various anticancer drugs. These observations suggest that autophagy counteracts druginduced apoptosis. We previously reported that in human melanoma and osteosarcoma cells, autophagy inhibitors, such as 3methyladenine and chloroquine increased the sensitivity to apoptosis induced by tumor necrosis factorrelated apoptosisinducing ligand (TRAIL). In the present study, we report that different autophagy inhibitors regulate the mitochondrial network and calcium (Ca2+) dynamics in these cells. We found that compared to tumor cells, normal fibroblasts were more resistant to the cytotoxicity of TRAIL and autophagy inhibitors used either alone or in combination. Notably, TRAIL increased the autophagic flux in the tumor cells, but not in the fibroblasts. Livecell imaging revealed that in tumor cells, TRAIL evoked modest mitochondrial fragmentation, while subtoxic concentrations of the autophagy inhibitors led to mitochondrial fusion. Cotreatment with TRAIL and subtoxic concentrations of the autophagy inhibitors resulted in severe mitochondrial fragmentation, swelling and clustering, similar to what was observed with autophagy inhibitors at toxic concentrations. The enhanced aberration of the mitochondrial network was preceded by a reduction in mitochondrial Ca2+ loading and storeoperated Ca2+ entry. On the whole, the findings of this study indicate that cotreatment with TRAIL and autophagy inhibitors leads to increased mitochondrial Ca2+ and network dysfunction in a tumorselective manner. Therefore, the coadministration of TRAIL and autophagy inhibitors may prove to be a promising tumortargeting approach for the treatment of TRAILresistant cancer cells.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Ósseas
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Osteossarcoma
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Cloroquina
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Cálcio
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Ligante Indutor de Apoptose Relacionado a TNF
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Melanoma
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article