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IFNγ sensitization to TRAIL-induced apoptosis in human thyroid carcinoma cells by upregulating Bak expression

Oncogene volume 23, pages 928–935 (2004)Cite this article

Abstract

TRAIL preferentially induces apoptosis in tumor cells and virus-infected cells. Unlike other tumor necrosis factor family members, TRAIL does not kill cells from most normal tissues and has thus been proposed as a promising new cancer treatment. Our study demonstrated that IFNγ combined with TRAIL can trigger apoptosis in vitro in several resistant thyroid tumor cell lines, such as thyroid anaplastic carcinoma cells (ARO cells), while either agent alone exerts only a minimal effect. We further tested this effect on a mouse thyroid tumor model, when in vivo tumor growth was also significantly inhibited by this combination. The mechanism of how IFNγ sensitized thyroid carcinoma cells to TRAIL-induced apoptosis was investigated by screening global gene alterations in ARO cells treated with IFNγ. Microarray data revealed that a proapoptotic gene, Bak, is markedly upregulated by IFNγ, and this was confirmed by RNase protection assay. Western blot analysis also showed a significant increase in Bak at the protein level. Upregulation of Bak and sensitization for apoptosis by IFNγ was blocked by overexpression of antisense Bak in ARO cells. Furthermore, overexpression of Bak sensitized ARO cell to TRAIL-induced apoptosis without the need for IFNγ pretreatment. This suggests that Bak is a regulatory molecule involved in IFNγ-facilitated TRAIL-mediated apoptosis in thyroid cancer cells.

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Acknowledgements

We gratefully acknowledge Dr A Chinnaiyan for the endotoxin-free human recombinant TRAIL, Dr Y Chen for the soluble recombinant human DR5, Dr JA Fagin for the ARO, FRO NPA human thyroid carcinoma cell lines, Dr H Eguchi for the antisense Bak expression vector (pRC/CMV), Dr J Bretz and Dr N Beeson for comments on the manuscript. This work was supported by the National Institutes of Health Grants R01 A137141, P60DK20572 and DK58771.

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Authors and Affiliations

  1. Department of Medicine, University of Michigan Medical Center, Ann Arbor, MI, USA

    Su He Wang, Emese Mezosi, Julie M Wolf, Zhengyi Cao, Saho Utsugi & James R Baker Jr

  2. Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, USA

    Paul G Gauger & Gerard M Doherty

  3. Center for Biologic Nanotechnology, University of Michigan Medical Center, Ann Arbor, MI, USA

    Su He Wang, Julie M Wolf, Zhengyi Cao & James R Baker Jr

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  1. Su He Wang
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  2. Emese Mezosi
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Correspondence to James R Baker Jr.

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Wang, S., Mezosi, E., Wolf, J. et al. IFNγ sensitization to TRAIL-induced apoptosis in human thyroid carcinoma cells by upregulating Bak expression. Oncogene 23, 928–935 (2004). https://doi.org/10.1038/sj.onc.1207213

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  • DOI: https://doi.org/10.1038/sj.onc.1207213

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