1. ¹INSERM Unité 685, Institut Universitaire d'Hématologie, Paris Cedex 10, France
2. ²AP-HP, Hôpital St Louis, Paris Cedex 10, France

Correspondence: Dr F Besançon, Institut de la Santé et de la Recherche Médicale, Unité 685, Hôpital St Louis, 1 avenue Claude Vellefaux, Paris Cedex 10 75475, France. E-mail: Francoise.Besancon@stlouis.inserm.fr

Received 5 April 2007; Revised 6 November 2007; Accepted 22 November 2007; Published online 17 December 2007.

Abstract

When administrated by isolated limb perfusion, tumor necrosis factor (TNF) is an efficient antitumor agent that improves drug penetration and destroys angiogenic vessels. Moreover, the pronounced potentiation of TNF-induced apoptosis by NF-B inhibitors suggest that these compounds could enhance TNF antitumor efficacy through direct induction of tumor cell apoptosis. Therefore, attempts at amplifying signaling pathways that mediate TNF antitumor effects could help to design combination therapies improving its efficiency. We report that nanomolar concentrations of all-trans retinoic acid (ATRA) amplify TNF-induced apoptosis in APL cells expressing a specific repressor of NF-B activation. This effect is abolished by the pan-caspase inhibitor, Z-VAD-fmk and by caspase-8 and -9 inhibitors. Cell death is accompanied by a drop of mitochondrial potential and by poly (ADP-ribose) polymerase (PARP) activation. Using specific PARP-1 inhibitors and siRNAs, we show that PARP-1 is essential for the synergistic apoptotic effect and c-Jun N-terminal kinase 1 (JNK1) activation triggered by the ATRA/TNF combination. JNK1 siRNAs reduce ATRA/TNF-induced apoptosis, mitochondrial release of cytochrome c and caspase-9 activation. Altogether, these results identify a novel mechanism of PARP-1-induced apoptosis, in which JNK1 provides a link between PARP-1 activation and mitochondrial pathway of caspase-9 activation. This study also suggests that inclusion of nanomolar doses of ATRA could be clinically beneficial in amplifying TNF-induced antitumor signals.