Potentiation of TRAILinduced cell death by nonsteroidal antiinflammatory drug in human hepatocellular carcinoma cells through the ER stressdependent autophagy pathway.
Oncol Rep
; 44(3): 1136-1148, 2020 09.
Article
em En
| MEDLINE
| ID: mdl-32705218
ABSTRACT
Hepatocellular carcinoma (HCC) is the most commonly diagnosed primary liver malignancy. The limited success with relapse of the disease in HCC therapy is frequently associated with the acquired resistance to anticancer drugs. To develop a strategy and design for overcoming the resistance of HCC cells to TNFrelated apoptosis inducing ligand (TRAIL)induced cell death, we evaluated the efficacy of a nonsteroidal antiinflammatory drug (NSAID) in combination with TRAIL against TRAILresistant HCC cells expressing a high level of CD44. We revealed by MTT and western blotting, respectively, that celecoxib (CCB), an NSAID, and 2,5dimethyl celecoxib (DMC), a noncyclooxygenase (COX)2 inhibitor analog of CCB, were able to sensitize TRAILresistant HCC cells to TRAIL, implicating a COXindependent mechanism. CCB dosedependently enhanced LC3II and reduced p62 levels through AMPK activation and inhibition of the Akt/mTOR pathway and upregulated expression of ATF4/CHOP, leading to activation of endoplasmic reticulum (ER) stressdependent autophagy. The TRAIL sensitization capacity of CCB in TRAILresistant HCC cells was abrogated by an ER stress inhibitor. In addition, we also revealed by flow cytometry and western blotting, respectively, that accelerated downregulation of TRAILmediated cFLIP expression, DR5 activation and CD44 degradation/downregulation by NSAID resulted in activation of caspases and poly(ADPribose) polymerase (PARP), leading to the sensitization of TRAILresistant HCC cells to TRAIL and thereby reversal of TRAIL resistance. From these results, we propose that NSAID in combination with TRAIL may improve the antitumor activity of TRAIL in TRAILresistant HCC, and this approach may serve as a novel strategy that maximizes the therapeutic efficacy of TRAIL for clinical application.
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Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Base de dados:
MEDLINE
Assunto principal:
Protocolos de Quimioterapia Combinada Antineoplásica
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Anti-Inflamatórios não Esteroides
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Carcinoma Hepatocelular
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Ligante Indutor de Apoptose Relacionado a TNF
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Neoplasias Hepáticas
Limite:
Humans
Idioma:
En
Revista:
Oncol Rep
Ano de publicação:
2020
Tipo de documento:
Article