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Research Articles: Therapeutics, Targets, and Development

Fanconi anemia D2 protein confers chemoresistance in response to the anticancer agent, irofulven

¹ Mary Babb Randolph Cancer Center, ² Department of Microbiology, Immunology, and Cell Biology, and ³ Department of Pathology, West Virginia University School of Medicine, Morgantown, West Virginia

Requests for reprints: Weixin Wang, Mary Babb Randolph Cancer Center, West Virginia University, 1835 Health Sciences South, P.O. Box 9300, Morgantown, WV 26506. Phone: 304-293-2243; Fax: 304-293-4667. E-mail: wwang{at}hsc.wvu.edu

Abstract

The Fanconi anemia-BRCA pathway of genes are frequently mutated or epigenetically repressed in human cancer. The proteins of this pathway play pivotal roles in DNA damage signaling and repair. Irofulven is one of a new class of anticancer agents that are analogues of mushroom-derived illudin toxins. Preclinical studies and clinical trials have shown that irofulven is effective against several tumor cell types. The exact nature of irofulven-induced DNA damage is not completely understood. Previously, we have shown that irofulven activates ATM and its targets, NBS1, SMC1, CHK2, and p53. In this study, we hypothesize that irofulven induces DNA double-strand breaks and FANCD2 may play an important role in modulating cellular responses and chemosensitivity in response to irofulven treatment. By using cells that are proficient or deficient for FANCD2, ATR, or ATM, we showed that irofulven induces FANCD2 monoubiquitination and nuclear foci formation. ATR is important in mediating irofulven-induced FANCD2 monoubiquitination. Furthermore, we showed that FANCD2 plays a critical role in maintaining chromosome integrity and modulating chemosensitivity in response to irofulven-induced DNA damage. Therefore, this study suggests that it might be clinically significant to target irofulven therapy to cancers defective for proteins of the Fanconi anemia-BRCA pathway. [Mol Cancer Ther 2006;5(12):3153–61]

Grant support: National Cancer Institute grant 5R03CA107979 (W. Wang).

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.

Note: Current address for E. Reed: Centers for Disease Control and Prevention, Atlanta, Georgia.

Received 7/20/06; revised 9/28/06; accepted 11/ 1/06.