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First published on January 11, 2005; DOI: 10.1124/mol.104.008797

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Received for publication November 3, 2004.
Revised December 16, 2004.
Accepted for publication January 7, 2005.

Cross-Resistance to Death Ligand-Induced Apoptosis in Cisplatin-Selected HeLa Cells Associated with Overexpression of DDB2 and Subsequent Induction of cFLIP

Chun-Ling Sun 1 Chuck C.-K. Chao 1*

1 Chang Gung University

* Address correspondence to: E-mail: cckchao{at}mail.cgu.edu.tw

Abstract

This work reports the involvement of DDB2, a component involved in the genomic repair of UV damage, in the cross-resistance of cisplatin-selected cell lines to death ligand-mediated apoptosis. The cisplatin-resistant cell line (HR3) exhibits enhanced expression of DDB2 and cross-resistance to UV-induced activation of apoptosis and caspases. This investigation further demonstrates that HR3 cells also exhibited cross-resistance to death ligands (Fas-inducing antibody and TNF-{alpha}). Depletion of the elevated DDB2 in HR3 cells sensitizes Fas-inducing antibody- and TNF-{alpha}-induced apoptosis. In contrast, the over-expression of DDB2 induces cFLIP expression and further attenuates death ligand-induced apoptosis. Moreover, RT-PCR and reporter assay indicated that DDB2 could increase both endogenous and exogenous cFLIP mRNA levels. Accordingly, the elimination of cFLIP by antisense oligonucleotides (ASO) suppresses DDB2 protection. These findings reveal that DDB2 regulates TNF signaling-mediated apoptosis via cFLIP and contributes to acquired cross-resistance. DDB2, while participating in DNA repair, functions as a negative regulator of apoptosis, and may therefore have a pivotal role in regulating immune response and cancer-therapeutic efficacy.


Key words: Tumor necrosis factor, Promoter analysis, Regulation of gene expression, Apoptosis, DNA damage and repair, Mechanisms of cell killing/apoptosis, Resistance


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[Abstract] [Full Text] [PDF]


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