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Involvement of DR4/JNK pathway-mediated autophagy in acquired TRAIL resistance in HepG2 cells
- Source :
- International journal of oncology. 49(5)
- Publication Year :
- 2016
-
Abstract
- Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent, a number of cancer cells demonstrate TRAIL resistance. To date, various molecular targets leading to TRAIL resistance have been elucidated by many researchers, but the mechanisms involved are still not fully understood. In the present study, we obtained TRAIL-resistant cells from the human hepatocellular carcinoma cell line HepG2 by exposing cells to recombinant human TRAIL (rhTRAIL), and determined a mechanism for TRAIL resistance. The selected TRAIL-resistant cells (HepG2-TR) were insensitive to rhTRAIL and triggered autophagy in response to rhTRAIL. The inhibition of autophagy by 3-methyladenine or the knockdown of ATG5 partially restored rhTRAIL-induced apoptosis and cytotoxicity, indicating that protective autophagy occurred in the cells. Notably, rhTRAIL-induced autophagy was mediated through DR4 in HepG2-TR cells, but not in parental HepG2 cells. In addition, the c-Jun N-terminal kinase was involved in DR4-mediated autophagy in HepG2-TR cells. Our results suggest a novel mechanism of TRAIL resistance which is regulated through alterations in DR4 function, which may extend our understanding of the mechanisms of TRAIL resistance.
- Subjects :
- 0301 basic medicine
Cancer Research
Carcinoma, Hepatocellular
Cell Survival
MAP Kinase Kinase 4
ATG5
Cell
Immunoblotting
Antineoplastic Agents
Apoptosis
Biology
TNF-Related Apoptosis-Inducing Ligand
03 medical and health sciences
medicine
Autophagy
Tumor Cells, Cultured
Humans
Liver Neoplasms
Cell cycle
Cell biology
Receptors, TNF-Related Apoptosis-Inducing Ligand
030104 developmental biology
medicine.anatomical_structure
Oncology
Drug Resistance, Neoplasm
Cancer cell
Tumor necrosis factor alpha
Signal transduction
Signal Transduction
Subjects
Details
- ISSN :
- 17912423
- Volume :
- 49
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- International journal of oncology
- Accession number :
- edsair.doi.dedup.....ed92dabf271ab2a551d070c81c013298