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Research Articles: Therapeutics, Targets, and Development

Treatment of colon cancer cells using the cytosine deaminase/5-fluorocytosine suicide system induces apoptosis, modulation of the proteome, and Hsp90ß phosphorylation

¹ Plateforme Protéomique IFR50, ² Centre National de la Recherche Scientifique and ³ Institut National de la Santé et de la Recherche Médicale Unité 638, ⁴ Faculté de Médecine, Université de Nice Sophia-Antipolis, Nice Cedex 2, France

Requests for reprints: Christian Baudoin, Faculté de Médecine, Unité INSERM U638, Université de Nice Sophia-Antipolis, Avenue de Valombrose, 06107 Nice Cedex 2, France. Phone: 33-49337-7704; Fax: 33-49381-9456. E-mail: baudoin{at}unice.fr

Abstract

The bacterial cytosine deaminase (CD) gene, associated with the 5-fluorocytosine (5FC) prodrug, is one of the most widely used suicide systems in gene therapy. Introduction of the CD gene within a tumor induces, after 5FC treatment of the animal, a local production of 5-fluorouracil resulting in intratumor chemotherapy. Destruction of the gene-modified tumor is then followed by the triggering of an antitumor immune reaction resulting in the regression of distant wild-type metastasis. The global effects of 5FC on colorectal adenocarcinoma cells expressing the CD gene were analyzed using the proteomic method. Application of 5FC induced apoptosis and 19 proteins showed a significant change in 5FC-treated cells compared with control cells. The up-regulated and down-regulated proteins include cytoskeletal proteins, chaperones, and proteins involved in protein synthesis, the antioxidative network, and detoxification. Most of these proteins are involved in resistance to anticancer drugs and resistance to apoptosis. In addition, we show that the heat shock protein Hsp90ß is phosphorylated on serine 254 upon 5FC treatment. Our results suggest that activation of Hsp90ß by phosphorylation might contribute to tumor regression and tumor immunogenicity. Our findings bring new insights into the mechanism of the anticancer effects induced by CD/5FC treatment. [Mol Cancer Ther 2007;6(10):2747–56]

Grant support: Institut National de la Santé et de la Recherche Médicale.

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.

⁵ http://www.expasy.org/tools/aldente/

Received 1/17/07; revised 6/11/07; accepted 9/ 4/07.