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Research Articles

Therapeutic targeting of nuclear receptor corepressor misfolding in acute promyelocytic leukemia cells with genistein

¹ Oncology Research Institute and ² Department of Medicine, ³ Graduate School of Integrative Sciences and Engineering, Yong Loo Lin School of Medicine, National University of Singapore and ⁴ Department of Oncology and Haematology, National University Hospital, Singapore, Singapore; and ⁵ Division of Hematology and Oncology, School of Medicine, Loma Linda University, Loma Linda, California

Requests for reprints: Matiullah Khan, Oncology Research Institute (ORI), Yong Loo Lin School of Medicine, National University of Singapore, 02-07, Center for Life Sciences, 28 Medical Drive, Singapore 117456. Phone: 65-6516-7283; Fax: 65-6873-9664. E-mail: nmimmk{at}nus.edu.sg

Abstract

We have recently reported that PML-RAR–induced misfolding of the N-CoR protein could be reversed by retinoic acid (RA), a therapeutic agent that promotes differentiation of acute promyelocytic leukemia (APL) cells. This finding suggests a role of misfolded N-CoR in the differentiation arrest of APL cells and highlights its significance as a potential molecular target in protein conformation–based therapy for APL. Based on this hypothesis, we investigated the therapeutic potential of several protein conformation modifiers on APL-derived cell lines NB4 and NB4-R1. Through a small-scale screening of these selected compounds, we identified genistein as a potent inhibitor of growth of both RA-sensitive and RA-resistant APL cells. Genistein inhibited the growth of NB4 cells through its collective regulatory effects on cell cycle progression, differentiation, and apoptosis. Genistein-induced apoptosis of NB4 cells was mediated by activation of caspase-9 and caspase-3 and was associated with a decrease in mitochondrial transmembrane potential and cytosolic release of cytochrome c. Genistein promoted differentiation of both RA-sensitive and RA-resistant NB4 cells and induced cell cycle arrest by blocking the G₂-M transition. Genistein up-regulated the expression of PML and N-CoR proteins, promoted degradation of PML-RAR, and reorganized the microspeckled distribution of PML oncogenic domains to a normal dot-like pattern in NB4 cells. Moreover, genistein significantly reversed the PML-RAR–induced misfolding of N-CoR protein by possibly inhibiting the selective phosphorylation-dependent binding of N-CoR to PML-RAR. These findings identify genistein as a potent modifier of N-CoR protein conformation and highlights its therapeutic potential in both RA-sensitive and RA-resistant APL cells. [Mol Cancer Ther 2007;6(8):2240–8]

Grant support: National Medical Research Council grant NMRC/0848/2004, in part by Singapore Stem Cell Consortium grant SSCC-06-04, Biomedical Research Council of Singapore (M. Khan), Singapore's Agency of Science, Technology, and Research graduate scholarship (A.P-P. Ng).

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: D.S. Nin and J.H. Fong contributed equally to this work.

⁶ Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 11/14/06; revised 5/ 9/07; accepted 6/29/07.