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TRAIL and inhibitors of apoptosis are opposing determinants for NF-κB-dependent, genotoxin-induced apoptosis of cancer cells

Oncogene volume 21, pages 260–271 (2002)Cite this article

Abstract

Opposing pro- and anti-apoptotic actions of TRAIL and the inhibitors of apoptosis (IAPs) contribute to the cell's decision to survive or die. We demonstrate that in H157 human lung carcinoma cells, etoposide and doxorubicin induce the NF-κB-dependent expression of both pro- and anti-apoptotic proteins including TRAIL and its death receptor, DR5, and IAPs. Inhibition of NF-κB activation in H157 cells in response to genotoxin resulted in loss of cell surface expression of TRAIL and DR5, aggressive growth and chemotherapy resistance of tumors in nude mice. Similar to the paracrine TRAIL response in H157 cells, the sensitivity of normal lung and breast epithelium and carcinomas to undergo genotoxin-induced apoptosis correlates strongly with cell surface expression of TRAIL. Suppression of TRAIL signaling by expression of the TRAIL decoy receptor, DcR1, confers chemoresistance to cancer cells. These findings demonstrate that TRAIL signaling via its death receptors is a significant contributor to genotoxin-induced apoptosis in human epithelial carcinomas.

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Author notes

  1. Aaron C Spalding and Robert M Jotte: Both authors contributed equally to this paper

Authors and Affiliations

  1. Department of Pharmacology, University of Colorado Cancer Center, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, 80262, Colorado, CO, USA

    Aaron C Spalding, Robert M Jotte & Gary L Johnson

  2. Department of Medicine, University of Colorado Cancer Center, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, 80262, Colorado, CO, USA

    Mark W Geraci

  3. Department of Neurology, University of Colorado Cancer Center, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, 80262, Colorado, CO, USA

    Penny Clarke & Kenneth L Tyler

  4. School of Pharmacy, University of Colorado Cancer Center, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, 80262, Colorado, CO, USA

    Robert I Scheinman

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  1. Aaron C Spalding
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Correspondence to Gary L Johnson.

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Spalding, A., Jotte, R., Scheinman, R. et al. TRAIL and inhibitors of apoptosis are opposing determinants for NF-κB-dependent, genotoxin-induced apoptosis of cancer cells. Oncogene 21, 260–271 (2002). https://doi.org/10.1038/sj.onc.1205048

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