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The Role of cIAP1 and XIAP in Apoptosis Induced by Tumor Necrosis Factor Alpha in Esophageal Squamous Cell Carcinoma Cells

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Abstract

Background

The inhibitor of apoptosis protein (IAP) family are reported to play important roles in cancer cells evading apoptosis. However, the significance of their expression in human esophageal squamous cell carcinoma (ESCC) cells remains uncertain.

Aims

The present study aimed to investigate the role of the IAP family members in tumor necrosis factor-α (TNF-α)-induced apoptosis of human ESCC cells.

Methods

Five human ESCC cell lines were pretreated with TNF-α, cycloheximide (CHX, protein synthesis inhibitor), epoxomicin (proteasome inhibitor). Apoptosis assay and protein study with Western blot testing were conducted. Knockdown experiments with IAP siRNA were conducted, and the effect on cell apoptosis was analyzed.

Results

Significant apoptosis was induced in five ESCC cell lines by TNF-α plus CHX stimulation, but not when treated with TNF-α or CHX alone. The protein expression levels of cIAP1 and XIAP were decreased by treatment with TNF-α in the presence of CHX, and the degree of cIAP1 and XIAP expression decrease was correlated with sensitivity to TNF-α plus CHX-induced apoptosis. Epoxomicin suppressed TNF-α plus CHX-induced degradation of survivin, cIAP1, and XIAP, in addition to apoptosis. A caspase inhibitor (z-VAD-fmk) suppressed TNF-α plus CHX-induced apoptosis, but did not suppress degradation of survivin, cIAP1, and XIAP. Furthermore, cIAP1 or XIAP siRNA transfected cells underwent apoptosis in response to treatment with TNF-α alone. Double knockdown of both genes resulted in further increased apoptosis.

Conclusion

cIAP1 and XIAP play an essential role in the resistance of ESCC cells against apoptosis.

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Abbreviations

CHX:

Cycloheximide

cIAP1:

Cellular IAP

FBS:

Fetal bovine serum

IAP:

Inhibitor of apoptosis

PI:

Propidium iodide

TNF-α:

Tumor necrosis factor-α

XIAP:

X-linked IAP

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Acknowledgments

This work was supported by Grant-in-Aid for Scientific Research (C) (26461988) and Grants-in-Aid for Young Scientists (B) (15K19903) from the Japan Society for the Promotion of Science.

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    Authors and Affiliations

    1. Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan

      Shoichiro Hikami, Atsushi Shiozaki, Maki Kitagawa-Juge, Daisuke Ichikawa, Toshiyuki Kosuga, Hirotaka Konishi, Shuhei Komatsu, Hitoshi Fujiwara, Kazuma Okamoto & Eigo Otsuji

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    1. Shoichiro Hikami
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    2. Atsushi Shiozaki
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    Correspondence to Atsushi Shiozaki.

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    The authors declare that they have no conflict of interest.

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    Shoichiro Hikami, Atsushi Shiozaki and Maki Kitagawa-Juge contributed equally to this work.

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    Hikami, S., Shiozaki, A., Kitagawa-Juge, M. et al. The Role of cIAP1 and XIAP in Apoptosis Induced by Tumor Necrosis Factor Alpha in Esophageal Squamous Cell Carcinoma Cells. Dig Dis Sci 62, 652–659 (2017). https://doi.org/10.1007/s10620-016-4430-9

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    • DOI: https://doi.org/10.1007/s10620-016-4430-9

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