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TRAIL induced survival and proliferation in cancer cells resistant towards TRAIL-induced apoptosis mediated by NF-κB

TRAIL induced survival and proliferation in cancer cells resistant towards TRAIL-induced... Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in cancer cells. Examining primary cells of children with untreated acute leukemia, TRAIL induced apoptosis in 50% of cells, but to our surprise attenuated spontaneous apoptosis in the remaining samples or, most importantly, even mediated proliferation. We therefore examined tumor cell lines of leukemic and nonleukemic origin with apoptosis resistance towards TRAIL because of absent Caspase-8 or dysfunctional FADD. In all cell lines tested, TRAIL treatment increased cell numbers in average to 163% within 4 days and accelerated doubling time from 24 to 19 h. TRAIL-mediated proliferation was completely abrogated by blockade of NF-κB activation using proteasome inhibitors or in RIP-negative, IKKγ-negative cells or in cells overexpressing dominant-negative IκBα. Our data describe the biological significance of TRAIL-mediated activation of NF-κB in cancer cells resistant to TRAIL-mediated apoptosis: TRAIL leads to an increase in tumor cell count by a prosurvival and possibly mitogenic function. Given the promising therapeutic potential of TRAIL as a novel anticancer drug, TRAIL-mediated survival or proliferation of target cells may restrict its use to apoptosis-sensitive tumors. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Oncogene Springer Journals

TRAIL induced survival and proliferation in cancer cells resistant towards TRAIL-induced apoptosis mediated by NF-κB

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References (10)

Publisher
Springer Journals
Copyright
Copyright © 2003 by Nature Publishing Group
Subject
Medicine & Public Health; Medicine/Public Health, general; Internal Medicine; Cell Biology; Human Genetics; Oncology; Apoptosis
ISSN
0950-9232
eISSN
1476-5594
DOI
10.1038/sj.onc.1206520
Publisher site
See Article on Publisher Site

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in cancer cells. Examining primary cells of children with untreated acute leukemia, TRAIL induced apoptosis in 50% of cells, but to our surprise attenuated spontaneous apoptosis in the remaining samples or, most importantly, even mediated proliferation. We therefore examined tumor cell lines of leukemic and nonleukemic origin with apoptosis resistance towards TRAIL because of absent Caspase-8 or dysfunctional FADD. In all cell lines tested, TRAIL treatment increased cell numbers in average to 163% within 4 days and accelerated doubling time from 24 to 19 h. TRAIL-mediated proliferation was completely abrogated by blockade of NF-κB activation using proteasome inhibitors or in RIP-negative, IKKγ-negative cells or in cells overexpressing dominant-negative IκBα. Our data describe the biological significance of TRAIL-mediated activation of NF-κB in cancer cells resistant to TRAIL-mediated apoptosis: TRAIL leads to an increase in tumor cell count by a prosurvival and possibly mitogenic function. Given the promising therapeutic potential of TRAIL as a novel anticancer drug, TRAIL-mediated survival or proliferation of target cells may restrict its use to apoptosis-sensitive tumors.

Journal

Oncogene – Springer Journals

Published: Jun 17, 2003

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