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Research Articles: Therapeutics, Targets, and Development

Selenium sensitizes MCF-7 breast cancer cells to doxorubicin-induced apoptosis through modulation of phospho-Akt and its downstream substrates

Departments of ¹ Cancer Chemoprevention and ² Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York

Requests for reprints: Clement Ip, Department of Cancer Chemoprevention, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-8875; Fax: 716-845-8100. E-mail: clement.ip{at}roswellpark.org

Abstract

Doxorubicin is an effective drug against breast cancer. However, the favorable therapeutic response to doxorubicin is often associated with severe toxicity. The present research was aimed at developing a strategy of increasing doxorubicin sensitivity so that lower doses may be used without compromising efficacy. The MCF-7 human breast cancer cell line currently in use in our laboratory did not respond to doxorubicin cell killing during a 24-h treatment period. By combining doxorubicin with selenium, we were successful in producing a brisk enhancement of apoptosis. We examined the effects of these two agents on Akt activation and found that selenium was capable of depressing doxorubicin-induced Akt phosphorylation. Several lines of evidence converged to support the notion that this effect is important in mediating the synergy between selenium and doxorubicin. Selenium was no longer able to sensitize cells to doxorubicin under a condition in which Akt was constitutively activated. Increased Akt phosphorylation following treatment with doxorubicin was accompanied by increased phosphorylation of glycogen synthase kinase 3ß (GSK3ß) and FOXO3A, which are substrates of Akt (both GSK3ß and FOXO3A lose their proapoptotic activities when they are phosphorylated). Selenium reduced the abundance of phospho-GSK3ß induced by doxorubicin, whereas chemical inhibition of GSK3ß activity muted the apoptotic response to the selenium/doxorubicin combination. Additional experiments showed that selenium increased the transactivation activity of FOXO3A, as evidenced by a reporter gene assay, as well as by the elevated expression of Bim (a target gene of FOXO3A). The functional significance of Bim was confirmed by the observation that RNA interference of Bim markedly reduced the potency of selenium/doxorubicin to induce apoptosis. [Mol Cancer Ther 2007;6(3):OF1–8

Grant support: National Cancer Institute grants CA 91990 (C. Ip) and P30 CA 16056 (Roswell Park Cancer Center).

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.

³ Unpublished data.

Received 10/17/06; revised 12/14/06; accepted 1/31/07.

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