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Molecular and Cellular Biology, January 2000, p. 205-212, Vol. 20, No. 1
0270-7306/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Increased Expression of Death Receptors 4 and 5 Synergizes the Apoptosis Response to Combined Treatment with Etoposide and TRAIL

Spencer B. Gibson,1,dagger Ryan Oyer,1 Aaron C. Spalding,1 Steven M. Anderson,2 and Gary L. Johnson1,3,*

Program in Molecular Signal Transduction, Division of Basic Sciences, National Jewish Medical and Research Center,1 and Departments of Pathology2 and Pharmacology,3 University of Colorado Medical School, Denver, Colorado 80206

Received 4 June 1999/Returned for modification 19 July 1999/Accepted 27 September 1999

Chemotherapeutic genotoxins induce apoptosis in epithelial-cell-derived cancer cells. The death receptor ligand TRAIL also induces apoptosis in epithelial-cell-derived cancer cells but generally fails to induce apoptosis in nontransformed cells. We show here that the treatment of four different epithelial cell lines with the topoisomerase II inhibitor etoposide in combination with TRAIL (tumor necrosis factor [TNF]-related apoptosis-inducing ligand) induces a synergistic apoptotic response. The mechanism of the synergistic effect results from the etoposide-mediated increase in the expression of the death receptors 4 (DR4) and 5 (DR5). Inhibition of NF-kappa B activation by expression of kinase-inactive MEK kinase 1(MEKK1) or dominant-negative Ikappa B (Delta Ikappa B) blocked the increase in DR4 and DR5 expression following etoposide treatment. Addition of a soluble decoy DR4 fusion protein (DR4:Fc) to cell cultures reduced the amount of etoposide-induced apoptosis in a dose-dependent manner. The addition of a soluble TNF decoy receptor (TNFR:Fc) was without effect, demonstrating the specificity of DR4 binding ligands in the etoposide-induced apoptosis response. Thus, genotoxin treatment in combination with TRAIL is an effective inducer of epithelial-cell-derived tumor cell apoptosis relative to either treatment alone.

* Corresponding author. Mailing address: Program in Molecular Signal Transduction, Division of Basic Sciences, National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO 80206. Phone: (303) 398-1772. Fax: (303) 398-1225. E-mail: johsonlab{at}njc.org.

dagger Present address: Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, MB, Canada R3E 6N9.

Molecular and Cellular Biology, January 2000, p. 205-212, Vol. 20, No. 1
0270-7306/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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