Molecular Mechanism Of Arctigenin Anti-tumor

Arctigenin is a dibenzylbutyrolactone lignan isolated from Arctium lappa L., It has been reported to exhibit antiviral activities, antitumor activities and anti-inflammatory activities, which is mainly mediated through its inhibitory effect on nuclear transcription factor-kappaB (NF-?B). But the role of arctigenin in signal transducer and activator of transcription 3 (STAT3) signaling pathways is still unclear. In present study, we investigated the effect of arctigenin on STAT3 pathway and evaluated whether suppression of STAT3 activity by arctigenin could sensitize cancer cells to a chemotherapeutic drug cisplatin. Our results show that arctigenin significantly suppressed both constitutively activated and IL-6-induced STAT3 phosphorylation and subsequent nuclear translocation in cancer cells. Inhibition of STAT3 tyrosine phosphorylation was found to be achieved through suppression of Src, JAK1 and JAK2, while suppression of STAT3 serine phosphorylation was mediated by inhibition of ERK activation. Pervanadate reversed the arctigenin-induced downregulation of STAT3 activation, suggesting the involvement of a protein tyrosine phosphatase. Indeed, arctigenin can obviously induce the expression of the PTP SHP-2. Furthermore, the constitutive activation level of STAT3 was found to be correlated to the resistance of cancer cells to cisplatin-induced apoptosis. Arctigenin downregulated the expression of STAT3-regulated gene products, including, cIAP2, Bcl-2, cyclinD1, and Mcl-1. It induced the inhibition of proliferation, and significantly potentiated the apoptotic effects of cisplatin in some cancer cells. These observations suggest a novel anticancer function of arctigenin and a potential therapeutic strategy of using arctigenin in combination with chemotherapeutic agents for cancer treatment.We further confirmed arctigenin suppressed both constitutive and inducible HSF1 in time-and dose-dependent manners and nuclear translocation, Arctigenin downregulated gene products of HSF1, including HSP70, HSP90 expression, but had no effect on HSF1 transcriptional level. Therefore, inhibition of HSF1 by arctigenin may directly interact between arctigenin and HSF1, our docking simulation tests showed arctigenin formed hydrogen bond network by SER230, SER248 and PRO276 of HSF1, the other residues involved in the reaction were in all HSF1 regulatory regions (amino acid sites 212-384), but SER326 residue involved in the activation of HSF1 was not related, inhibition of HSF1 by arctigenin is selective.Therefore, the molecular mechanism of arctigenin antitumor may be that the non-oncogene protein HSF1 regulates oncogene protein STAT3.