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Detachment-induced upregulation of XIAP and cIAP2 delays anoikis of intestinal epithelial cells

Oncogene volume 25, pages 7680–7690 (2006)Cite this article

Abstract

Detachment of normal epithelial cells from the extracellular matrix triggers apoptosis, a phenomenon called anoikis. Conversely, carcinoma cells tend to be relatively more anoikis-resistant than their normal counterparts, and this increased resistance represents a critical feature of the malignant phenotype. Mechanisms that control susceptibility and resistance to anoikis are not fully understood. It is now known that detachment of non-malignant epithelial cells triggers both pro- and antiapoptotic signals, and it is the balance between these signals and the duration of detachment that determine further fate of the cells. Detachment-induced antiapoptotic events delay anoikis and if cells reattach relatively soon after detachment they survive. Direct regulators of apoptosis responsible for this delay of anoikis are unknown. We found that detachment of non-malignant intestinal epithelial cells triggers upregulation of inhibitors of apoptosis protein (IAP) family, such as X-chromosome-linked inhibitor of apoptosis protein and cellular inhibitor of apoptosis-2 (cIAP2). We demonstrated that this upregulation requires detachment-dependent activation of the transcription factor nuclear factor-κB. We further observed that various IAP antagonists accelerate anoikis, indicating that upregulation of the IAPs delays detachment-triggered apoptosis. We conclude that the IAPs are important regulators of the balance between detachment-triggered life and death signals. Perhaps, not by coincidence, these proteins are often upregulated in carcinomas, tumors composed of cells that tend to be anoikis-resistant.

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Acknowledgements

This work was supported by The Terry Fox Foundation (through The National Cancer Institute of Canada, Grant no. 015397). Hongbing Li is a recipient of a Postdoctoral Traineeship Award from the Dalhousie Cancer Research Training Program. Byong Hoon Yoo is a recipient of a Postdoctoral Research Fellowship from the IWK Health Centre. We are grateful to Dr X Wang for the Smac expression vector.

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Authors and Affiliations

  1. Departments of Pediatrics and Biochemistry and Molecular Biology, Atlantic Research Centre, Dalhousie University, Halifax, Nova Scotia, Canada

    Z Liu, H Li, X Wu, B H Yoo & K V Rosen

  2. Departments of Pediatrics and Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada

    S R Yan & A W Stadnyk

  3. Department of Pathology, Research Institute, International Medical Center of Japan, Toyama, Shinjyuku-ku, Tokyo, Japan

    T Sasazuki & S Shirasawa

  4. Aegera Oncology Inc., Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada

    E C LaCasse

  5. Solange Gauthier – Karsh Molecular Genetics Laboratory, Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada

    R G Korneluk

  6. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada

    R G Korneluk

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  1. Z Liu
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Liu, Z., Li, H., Wu, X. et al. Detachment-induced upregulation of XIAP and cIAP2 delays anoikis of intestinal epithelial cells. Oncogene 25, 7680–7690 (2006). https://doi.org/10.1038/sj.onc.1209753

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