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Research Articles: Therapeutics, Targets, and Development

Dicoumarol down-regulates human PTTG1/Securin mRNA expression through inhibition of Hsp90

¹ Instituto de Recursos Naturales y Agrobiología de Sevilla and ² Centro Andaluz de Biología del Desarrollo, Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Seville, Spain

Requests for reprints: Agustín Hernández, Centro Andaluz de Biología Molecular y Medicina Regenerativa, Consejo Superior de Investigaciones Científicas, Avenida Américo Vespucio s/n, Seville 41092, Spain. Phone: 34-954-468-004; Fax: 34-954-461-664. E-mail: ahernan{at}cica.es

Abstract

Securin, the natural inhibitor of sister chromatid untimely separation, is a protooncogene overexpressed in tumors. Its protein levels correlate with malignancy and metastatic proneness. Dicoumarol, a long-established oral anticoagulant, is a new Hsp90 inhibitor that represses PTTG1/Securin gene expression and provokes apoptosis through a complex trait involving both intrinsic and extrinsic pathways. Dicoumarol activity as an Hsp90 inhibitor is confirmed by smaller levels of Hsp90 clients in treated cells and inhibition of in vivo heat shock luciferase activity recovery assays. Likewise, established Hsp90 inhibitors (17-allylamino-geldanamycin and novobiocin) repress PTTG1/Securin gene expression. Also, overexpression of human Hsp90 in yeast makes them hypersensitive to dicoumarol. Both apoptosis and PTTG1/Securin gene repression exerted by dicoumarol in cancer cells are independent of three of the most important signaling pathways affected by Hsp90 inhibition: nuclear factor-B, p53, or Akt/protein kinase B signaling pathways. However, effects on PTTG1/Securin could be partially ascribed to inhibition of the Ras/Raf/extracellular signal-regulated kinase pathway. Overall, we show that expression of PTTG1/Securin gene is Hsp90 dependent and that dicoumarol is a bona fide Hsp90 inhibitor. These findings are important to understand the mode of action of Hsp90 inhibitors, mechanisms of action of dicoumarol, and Securin overexpression in tumors. [Mol Cancer Ther 2008;7(3):474–82]

Grant support: Spanish Ministry of Education grants SAF02-0264-C03-02 and SAF2005-07713-C03-02; Andalusian Regional Government Grant-in-Aid for Incorporation of Researchers (A. Hernández).

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 J.A. Pintor-Toro: Centro Andaluz de Biología Molecular y Medicina Regenerativa, Consejo Superior de Investigaciones Científicas, Avenida Américo Vespucio s/n, Seville 41092, Spain. Current address for J.A. Bernal: Cancer Research UK, Department of Oncology, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 2XZ, United Kingdom.

³ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 7/ 8/07; revised 10/29/07; accepted 1/21/08.