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  • Original Paper
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Interferon-α sensitizes human hepatoma cells to TRAIL-induced apoptosis through DR5 upregulation and NF-κB inactivation

Oncogene volume 22, pages 1653–1662 (2003)Cite this article

Abstract

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, induces apoptosis in a variety of cancer cells with little or no effect on normal cells. Human hepatoma cells, however, are resistant to TRAIL-induced apoptosis. Since interferon-α (IFN-α) is capable of enhancing TNF-α-induced apoptosis in certain cancer cells, we evaluated the effect of IFN-α on TRAIL-induced apoptosis of human hepatoma cells. IFN-α pretreatment enhanced TRAIL-induced apoptosis of HuH-7 and Hep3B cells, in which IFN-α upregulated the expression of DR5, a death receptor of TRAIL, and downregulated the expression of survivin, which has an antiapoptotic function. In contrast, IFN-α did not enhance TRAIL-induced apoptosis of HepG2 cells, in which expression of DR5 and survivin was not affected by IFN-α. On the other hand, TRAIL activated NF-κB composed of RelA-p50 heterodimer, a key transcription factor regulating cell survival, in HuH-7 and HepG2 cells. However, IFN-α pretreatment repressed the TRAIL-mediated activation of NF-κB and decreased its transcriptional activity in HuH-7 but not in HepG2 cells. Moreover, IFN-α pretreatment clearly augmented TRAIL-mediated caspase-8 activation in HuH-7 cells. Our results suggest that IFN-α could sensitize certain human hepatoma cells to TRAIL-induced apoptosis by stimulating its death signaling and by repressing the survival function in these cells.

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Abbreviations

EMSA:

electrophoretic mobility shift assay

FADD:

Fas-associated death domain

FLIP:

FLICE-inhibitory protein

IAP:

inhibitor of apoptosis

IETD-pNA:

N-acetyl-Ile-Glu-Thr-Asp-p-nitroaniline

IFN-α:

interferon-α

TNF:

tumor necrosis factor

TRAIL:

tumor necrosis factor-related apoptosis-inducing ligand

XIAP:

X-chromose–linked IAP

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Acknowledgements

We thank Prof. T Tokuhisa (Department of Developmental Genetics, Chiba University, Japan) for generously providing pCR2FL.

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Authors and Affiliations

  1. First Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1, Sakamoto, Nagasaki, 852-8501, Japan

    Masaya Shigeno, Tatsuki Ichikawa, Atsushi Kawakami, Seigou Abiru, Seiji Miyazoe, Yuichi Nakagawa, Hiroki Ishikawa, Keisuke Hamasaki, Keisuke Nakata & Katsumi Eguchi

  2. Health Research Center, Nagasaki University, 1-7-1, Sakamoto, Nagasaki, 852-8501, Japan

    Kazuhiko Nakao & Nobuko Ishii

  3. Department of Clinical Pharmacology, Nagasaki University, 1-7-1, Sakamoto, Nagasaki, 852-8501, Japan

    Kasumi Suzuki

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  1. Masaya Shigeno
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  2. Kazuhiko Nakao
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Correspondence to Katsumi Eguchi.

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Shigeno, M., Nakao, K., Ichikawa, T. et al. Interferon-α sensitizes human hepatoma cells to TRAIL-induced apoptosis through DR5 upregulation and NF-κB inactivation. Oncogene 22, 1653–1662 (2003). https://doi.org/10.1038/sj.onc.1206139

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