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Molecular & Cellular Proteomics 7:2311-2322, 2008.
© 2008 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

Comparative Proteomics Study Reveals That Bacterial CpG Motifs Induce Tumor Cell Autophagy in Vitro and in Vivo^*,S

Samuel Bertin^,, Michel Samson^,,¶, Catherine Pons^,, Jean-Marie Guigonis^,¶, Adolfo Gavelli^,,||, Patrick Baqué^,,**, Nicole Brossette^,, Sophie Pagnotta^,, Jean-Ehrland Ricci^, and Valérie Pierrefite-Carle^,,¶¶

From the INSERM, Unité 638, Nice F-06107, France, Université de Nice Sophia Antipolis, Faculté de Médecine, Nice F-06107, France, ^¶ Plateforme protéomique, IFR50, Nice F-06107, France, ^|| Service de Chirurgie Générale et Digestive, Centre Hospitalier Princesse Grace, MC-98000 Monaco, Monaco, ^** Service de Chirurgie d'Urgence, Hôpital St. Roch, Rue Pierre Devoluy, Nice F-06107, France, Centre Commun de Microscopie Appliquée, Parc Valrose, Nice F-06108, France, and INSERM, U895, Centre Méditerranéen de Médecine Moléculaire (C3M), Cell Death and Survival AVENIR team, Nice F-06204 Cedex 3, France

Unmethylated CpG dinucleotides, present in bacterial DNA, are recognized in vertebrates via the Toll-like receptor 9 (TLR9) and are known to act as an anticancer agent by stimulating immune cells to induce a proinflammatory response. Although the effects of CpG-oligodeoxynucleotides (CpG-ODNs) in immune cells have been widely studied, little is known regarding their molecular effects in TLR9-positive tumor cells. To better understand the role of these bacterial motifs in cancer cells, we analyzed proteome modifications induced in TLR9-positive tumor cells in vitro and in vivo after CpG-ODN treatment in a rat colon carcinoma model. Proteomics analysis of tumor cells by two-dimensional gel electrophoresis followed by mass spectrometry identified several proteins modulated by bacterial CpG motifs. Among them, several are related to autophagy including potential autophagic substrates. In addition, we observed an increased glyceraldehyde-3-phosphate dehydrogenase expression, which has been shown to be sufficient to trigger an autophagic process. Autophagy is a self-digestion pathway whereby cytoplasmic material is sequestered by a structure termed the autophagosome for subsequent degradation and recycling. As bacteria are known to trigger autophagy, we assessed whether bacterial CpG motifs might induce autophagy in TLR9-positive tumor cells. We showed that CpG-ODN can induce autophagy in rodent and human tumor cell lines and was TLR9-dependent. In addition, an increase in the number of autophagosomes can also be observed in vivo after CpG motif intratumoral injection. Our findings bring new insights on the effect of bacterial CpG motifs in tumor cells and may be relevant for cancer treatment and more generally for gene therapy approaches in TLR9-positive tissues.

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