Inhibiting TRAF2-mediated Activation of NF-κB Facilitates Induction of AP-1

The compound 5-(4-methoxyarylimino)-2-N-(3,4-dichlorophenyl)3-oxo-1,2,4-thiadiazolidine (P-3-25) is known to possess anti-bacterial, anti-fungal, and anti-tubercular activities. In this report, we provide evidence that P-3-25 inhibits NF-kappa B, known to induce inflammatory and tumorigenic responses. It activates AP-1, another transcription factor. It inhibits TRAF2-mediated NF-kappa B activation but not TRAF6-mediated NF-kappa B DNA binding by preventing its association with TANK ( TRAF for NF-kappa B). It facilitates binding of MEKK1 with TRAF2 and thereby activates JNK and AP-1. We provide evidence, for the first time, that suggests that the interaction of P3-25 with TRAF2 leads to inhibition of the NF-kappa B pathway and activation of AP-1 pathway. These results suggest novel approaches to design of P3-25 as an anti-cancer/inflammatory drug for therapy through regulation of the TRAF2 pathway.