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Research Articles: Therapeutics, Targets, and Development

Arsenic trioxide decreases AKT protein in a caspase-dependent manner

Lady Davis Institute for Medical Research, Segal Cancer Center, McGill University, Montreal, Quebec, Canada

Requests for reprints: Wilson H. Miller, Jr., Lady Davis Institute for Medical Research, Segal Cancer Center, McGill University, 3755 Cote Ste Catherine Road, Montreal, Quebec, Canada H3T 1E2. Phone: 514-340-8222, ext. 4365; Fax: 514-340-7576. E-mail: wmiller{at}ldi.jgh.mcgill.ca

Abstract

Arsenic trioxide (As₂O₃) is used clinically to treat acute promyelocytic leukemia but is less successful in other malignancies. To identify targets for potential combination therapies, we have begun to characterize signaling pathways leading to As₂O₃-induced cytotoxicity. Previously, we described the requirement for a reactive oxygen species–mediated, SEK1/c-Jun NH₂-terminal kinase (JNK) pathway to induce apoptosis. AKT inhibits several steps in this pathway; therefore, we postulated that As₂O₃ might decrease its activity. Indeed, As₂O₃ decreases not only AKT activity but also total AKT protein, and sensitivity to As₂O₃ correlates with the degree of AKT protein decrease. Decreased AKT expression further correlates with JNK activation and the release of AKT from the JNK-interacting protein 1 scaffold protein known to assemble the mitogen-activated protein kinase cascade. We found that As₂O₃ regulates AKT protein stability without significant effects on its transcription or translation. We show that As₂O₃ decreases AKT protein via caspase-mediated degradation, abrogated by caspase-6, caspase-8, caspase-9, and caspase-3 inhibitors but not proteosome inhibitors. Furthermore, As₂O₃ enhances the ability of a heat shock protein 90 inhibitor to decrease AKT expression and increase growth inhibition. This suggests that As₂O₃ may be useful in combination therapies that target AKT pathways or in tumors that have constitutively active AKT expression. [Mol Cancer Ther 2008;7(6):1680–7]

Grant support: Canadian Institute of Health Research and Samuel Waxman Cancer Research Foundation (W.H. Miller, Jr.).

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.

¹ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 10/ 4/07; revised 3/11/08; accepted 3/16/08.