Securinine Inhibits Phosphorylation Of STAT3and Growth Of STAT3-dependent Cancer Cells

JAK-STAT signaling pathway is widespread in mammals; it is one of cancer associated signaling that has been well understood. JAK-STAT signaling regulates lots of genes involved in the occurrence and development of tumors. STAT3plays essential role in tumor cell proliferation, anti-apoptosis, angiogenesis, and invasion. STAT3is usually constitutively activated in numerous malignant tumors, such as prostate cancer, breast cancer, colon cancer, lung cancer, gastric cancer, etc. Numerous research have been revealed that specific inhibition of STAT3signaling generally down-regulate the expression of tumor associated protein, which leads to inbibite the proliferation, survival and invasion of tumor. JAK-STAT signaling pathway has became a key target for anti-tumor drug exploration. Securinine is a main alkaloid natural products of Securinega suffruticosa(Pall.)Rehd. It was discovered from STAT3and NF-kB dual signaling based bigh-throuhput drug screening system. Preliminary validation was performed at the molecular level, which shows that it has the function of inhibiting STAT3activity, and no obvious inhibition to the NF-κB signal.In this study, we focused on the mechanisms that were involved in the anti-tumor acitvities of Securinine by assessing its function on STAT3signaling pathway. We first determined the effection of Securinine on STAT3signaling activity in A549R cell line which stably expressing a STAT3response element driving luciferase repoter. We found that, Securinine shows significant STAT3inhibition activity with low cell toxicity. Further investigation provided that, in STAT3signaling-dependent DU145and MDA-MB-468cell lines, Securinine could effectively inhibit STAT3activition and down-regulate expressions of its downstreams genes involving in cell survival and cell cycle, such as c-Myc and CyclinDl, which leads to inhibit cell growth and induce cell apoptosis. On the other hand, Securinine shows less toxicity on normal human cells. Further study found that, Securinine blocks the upstream JAK1and JAK2activity. Securinine inhibites cytokine IL-6and IFNs induced JAK-STAT activation. Furthermore, Securinine blocks JAK1-JH1and JAK2-JH1tyrosine kinase domain overexpression induced STAT3and STAT1 activation. Cell migration experiments show that Securinine can inhibit some process of tumorigenesis.Finally, the present study demonstrated that Securinine has anti-tumor activity through selectively blocks JAK1and JAK2activition. The present data partially elaborated the mechanism of its anti-tumor activities and may help us to fiirther optimize the structure of the compound and improve its anti-tumor activity, and then reduce its cytotoxicity.