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

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...

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Bibliographic Details
Published in:Molecular cancer therapeutics 2007-01, Vol.6 (1), p.362-369
Main Authors: Soto-Cerrato, Vanessa, Viñals, Francesc, Lambert, James R, Kelly, Julie A, Pérez-Tomás, Ricardo
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - pharmacology
Apoptosis - drug effects
Apoptosis Regulatory Proteins - metabolism
Breast Neoplasms - genetics
Breast Neoplasms - pathology
Cytokines - genetics
Cytokines - metabolism
Gene Expression Profiling
Gene Expression Regulation, Neoplastic - drug effects
Genes, Neoplasm
Glycogen Synthase Kinase 3 - metabolism
Glycogen Synthase Kinase 3 beta
Growth Differentiation Factor 15
Humans
Prodigiosin - pharmacology
Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism
RNA, Messenger - genetics
RNA, Messenger - metabolism
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
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Summary: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-3beta (GSK-3beta) activation, which correlated with NAG-1 expression. Prodigiosin-induced apoptosis was recovered by inhibiting GSK-3beta, which might be due, at least in part, to the blockade of the GSK-3beta-dependent up-regulation of death receptors 4 and 5 expression. These findings suggest that prodigiosin-mediated GSK-3beta activation is a key event in regulating the molecular pathways that trigger the apoptosis induced by this anticancer agent.
ISSN:1535-7163
1538-8514