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Research Articles: Therapeutics, Targets, and Development

Active roles for inhibitory B kinases and β in nuclear factor-B–mediated chemoresistance to doxorubicin

¹ Lineberger Comprehensive Cancer Center and ² Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Requests for reprints: Hong J. Kim, Lineberger Comprehensive Cancer Center and Department of Surgery, University of North Carolina at Chapel Hill, 3010 Old Clinic Building, CB 7213, Chapel Hill, NC 27599-7213. Phone: 919-966-5221; Fax: 919-966-8806. E-mail: kimhj{at}med.unc.edu

Abstract

Chemotherapy agents have been shown to induce the transcription factor nuclear factor-B (NF-B) and subsequent chemoresistance in fibrosarcomas and other cancers. The mechanism of NF-B-mediated chemoresistance remains unclear, with a previous report suggesting that doxorubicin induces this response independent of the inhibitory B kinases (IKK). Other studies have indicated that IKKβ, but not IKK, is required. Mouse embryo fibroblasts devoid of IKK, IKKβ, or both subunits (double knockout) were treated with doxorubicin. The absence of either IKK or IKKβ or both kinases resulted in impaired induction of NF-B DNA-binding activity in response to doxorubicin. To provide a valid clinical correlate, HT1080 human fibrosarcoma cells were transfected with small interference RNA specific for IKK or IKKβ and then subsequently treated with doxorubicin. Knockdown of IKK severely impaired the ability of doxorubicin to initiate NF-B DNA-binding activity. However, a decrease in either IKK or IKKβ resulted in decreased phosphorylation of p65 in response to doxorubicin. The inhibition of doxorubicin-induced NF-B activation by the knockdown of either catalytic subunit resulted in increased cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase and increased apoptosis when compared with doxorubicin alone. The results of this study validate current approaches aimed at NF-B inhibition to improve clinical therapies. Moreover, we show that IKK plays a critical role in NF-B-mediated chemoresistance in response to doxorubicin and may serve as a potential target in combinational strategies to improve chemotherapeutic response. [Mol Cancer Ther 2008;7(7):1827–35]

Grant support: R01-CA73756, R01-CA75080, K08-CA098240, GI SPORE P50-CA10699-01, and T32-CA09688. Research was supported from both laboratories (H.J. Kim and A.S. Baldwin) equally.

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.

Received 4/ 2/08; accepted 4/23/08.