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Research Articles: Therapeutics, Targets, and Development

Prodigiosin induces the proapoptotic gene NAG-1 via glycogen synthase kinase-3ß activity in human breast cancer cells

¹ Department of Pathology and Experimental Therapeutics, Cancer Cell Biology Research Group and ² Departament de Ciències Fisiològiques II, Campus de Bellvitge, Universitat de Barcelona, Barcelona, Spain; and ³ Department of Pathology, University of Colorado Denver and Health Science Center, Aurora, Colorado

Requests for reprints: Ricardo Pérez-Tomás, Department of Pathology and Experimental Therapeutics, Cancer Cell Biology Research Group, Universitat de Barcelona, Pavelló Central, 5a planta, LR 5101 C/Feixa Llarga s/n, E 08907 L'Hospitalet, Barcelona, Spain. Phone: 34-934024288; Fax: 34-934029082. E-mail: rperez{at}ub.edu

Abstract

Prodigiosin (2-methyl-3-pentyl-6-methoxyprodigiosene) is a bacterial metabolite that has anticancer and antimetastatic properties. However, the molecular mechanisms responsible for these abilities are not fully understood. Gene expression profiling of the human breast cancer cell line MCF-7 treated with prodigiosin was analyzed by cDNA array technology. The majority of the significantly modified genes were related to apoptosis, cell cycle, cellular adhesion, or transcription regulation. The dramatic increase of the nonsteroidal anti-inflammatory drug-activated gene 1 (NAG-1) made this gene an interesting candidate regarding the possible mechanism by which prodigiosin induces cytotoxicity in MCF-7 cells. Our results show that prodigiosin triggers accumulation of the DNA-damage response tumor-suppressor protein p53 but that NAG-1 induction was independent of p53 accumulation. Moreover, prodigiosin caused AKT dephosphorylation and glycogen synthase kinase-3ß (GSK-3ß) activation, which correlated with NAG-1 expression. Prodigiosin-induced apoptosis was recovered by inhibiting GSK-3ß, which might be due, at least in part, to the blockade of the GSK-3ß–dependent up-regulation of death receptors 4 and 5 expression. These findings suggest that prodigiosin-mediated GSK-3ß activation is a key event in regulating the molecular pathways that trigger the apoptosis induced by this anticancer agent. [Mol Cancer Ther 2007;6(1):362–9]

Grant support: Ministerio de Ciencia y Tecnología and European Union grant SAF2001-3545 (R. Pérez-Tomás) and American Cancer Society Research Scholar award RSG-04-170-01-CNE (J.R. Lambert).

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.

Received 5/ 9/06; revised 10/13/06; accepted 11/27/06.