A PARP-1/JNK1 cascade participates in the synergistic apoptotic effect of TNF[alpha] and all-trans retinoic acid in APL cells

When administrated by isolated limb perfusion, tumor necrosis factor [alpha] (TNF[alpha]) is an efficient antitumor agent that improves drug penetration and destroys angiogenic vessels. Moreover, the pronounced potentiation of TNF[alpha]-induced apoptosis by NF-[kappa]B inhibitors suggest that these compounds could enhance TNF[alpha] antitumor efficacy through direct induction of tumor cell apoptosis. Therefore, attempts at amplifying signaling pathways that mediate TNF[alpha] antitumor effects could help to design combination therapies improving its efficiency. We report that nanomolar concentrations of all-trans retinoic acid (ATRA) amplify TNF[alpha]-induced apoptosis in APL cells expressing a specific repressor of NF-[kappa]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[alpha] combination. JNK1 siRNAs reduce ATRA/TNF[alpha]-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[alpha]-induced antitumor signals. [PUBLICATION ABSTRACT]