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J. Biol. Chem., Vol. 280, Issue 9, 7634-7644, March 4, 2005

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Tumor Necrosis Factor -dependent Drug Resistance to Purine and Pyrimidine Analogues in Human Colon Tumor Cells Mediated through IKK^*

Ling-Chi Wang, Cindy Yen Okitsu, and Ebrahim Zandi

From the Department of Molecular Microbiology and Immunology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine at USC, Los Angeles, California 90033

Development of drug resistance in cancer is one of the main challenges in chemotherapy, and many mechanisms are still unknown. In this study, we show that tumor necrosis factor (TNF) increases postdrug survival from 5-fluoro-2'-deoxyuridine (FdUrd) in two human colon tumor cell lines. This resulted in the development of drug-resistant cells in a TNF-dependent manner. Interestingly, although the drug-resistant cells were selected using FdUrd, they are also resistant to a number of other antimetabolites in the DNA synthesis pathway in a TNF-dependent manner. Only in the drug-resistant cells (p35-colo201) TNF treatment resulted in G₀-G₁ arrest but not in the parental colo201 and other cell types. Blocking TNF-induced cell cycle arrest sensitized drug-resistant cells to FdUrd. TNF-induced cell cycle arrest required IKK. IKK inhibition by a small molecule inhibitor or by the knockdown of IKK, IKK, or RelA/p65 using siRNA, but not the inhibition of JNK, MEK, p38, or caspase-8 pathways, blocked TNF-induced G₀-G₁ arrest and restored sensitivity to FdUrd of drug-resistant cells. TNF reduced the transcripts and protein levels of phosphorylated retinoblastoma protein (Rb), Rb, E2F1, and Cdk4 only in drug-resistant p35-colo201 cells. This effect of TNF was reversed by IKK inhibitor, suggesting that TNF-induced cell cycle arrest is probably due to the reduction of Rb, E2F1, and Cdk4. Taken together, this study shows that, in vitro, TNF-induced cell cycle arrest through IKK can provide a mechanism for the development of drug resistance to anti-cancer drugs, purine and pyrimidine analogues.

Received for publication, November 29, 2004

^* This work was supported by a grant from the Concern Foundation (to E. Z.) and Norris Cancer Center funds. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

A 2001 PEW Scholar; supported by National Institutes of Health Grant R01 MG065325. To whom correspondence should be addressed: USC/Norris Comprehensive Cancer Center, 1441 Eastlake Ave., Norris 6429, Los Angeles, CA 90033. Tel.: 323-865-0644; Fax: 323-865-0645; E-mail: Zandi{at}usc.edu.

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