Dataset Information

Homo sapiens

ABSTRACT: MicroRNA expression profile in TRAIL-sensitive and -resistant H460 cells

PROVIDER: PRJNA241076 | ENA |

REPOSITORIES: ENA

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Publications

A set of NF-κB-regulated microRNAs induces acquired TRAIL resistance in lung cancer.

Jeon Young-Jun YJ Middleton Justin J Kim Taewan T Laganà Alessandro A Piovan Claudia C Secchiero Paola P Nuovo Gerard J GJ Cui Ri R Joshi Pooja P Romano Giulia G Di Leva Gianpiero G Lee Bum-Kyu BK Sun Hui-Lung HL Kim Yonghwan Y Fadda Paolo P Alder Hansjuerg H Garofalo Michela M Croce Carlo M CM

Proceedings of the National Academy of Sciences of the United States of America 20150615 26

TRAIL (TNF-related apoptosis-inducing ligand) is a promising anticancer agent that can be potentially used as an alternative or complementary therapy because of its specific antitumor activity. However, TRAIL can also stimulate the proliferation of cancer cells through the activation of NF-κB, but the exact mechanism is still poorly understood. In this study, we show that chronic exposure to subtoxic concentrations of TRAIL results in acquired resistance. This resistance is associated with the i ...[more]

PMID: 26080425

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Project description:Dysregulation of the mitochondrial signaling pathway of apoptosis induction represents a major hurdle in tumor therapy. The objective of the presented work was to investigate the role of the intrinsic (mitochondrial) apoptotic pathway in the non-small lung cancer cell line NCI-H460 upon induction of apoptosis using the highly bioactive TRAIL derivative Db-scTRAIL. NCI-H460 cells were TRAIL sensitive but an only about 3 fold overexpression of Bcl-2 was sufficient to induce a highly TRAIL resistant phenotype, confirming that the mitochondrial pathway is crucial for TRAIL-induced apoptosis induction. TRAIL resistance was paralleled by a strong inhibition of caspase-8, -9 and -3 activities and blocked their full processing. Notably, especially the final cleavage steps of the initiator caspase-8 and the executioner caspase-3 were effectively blocked by Bcl-2 overexpression. Caspase-9 knockdown failed to protect NCI-H460 cells from TRAIL-induced cell death, suggesting a minor role of this initiator caspase in this apoptotic pathway. Rather, knockdown of the XIAP antagonist Smac resulted in enhanced caspase-3 degradation after stimulation of cells with TRAIL. Of note, downregulation of XIAP had only limited effects on TRAIL sensitivity of wild-type NCI-H460 cells, but resensitized Bcl-2 overexpressing cells for TRAIL-induced apoptosis. In particular, XIAP knockdown in combination with TRAIL allowed the final cleavage step of caspase-3 to generate the catalytically active p17 fragment, whose production was otherwise blocked in Bcl-2 overexpressing cells. Together, our data strongly suggest that XIAP-mediated inhibition of final caspase-3 processing is the last and major hurdle in TRAIL-induced apoptosis in NCI-H460 cells, which can be overcome by Smac in a Bcl-2 level dependent manner. Quantitative investigation of the XIAP/Smac interplay using a mathematical model approach corroborates our experimental data strengthening the suggested roles of XIAP and Smac as critical determinants for TRAIL sensitivity.

Dataset Information

Homo sapiens

Publications

A set of NF-κB-regulated microRNAs induces acquired TRAIL resistance in lung cancer.

Similar Datasets

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