3-Deoxy-2β,16-dihydroxynagilactone E, a natural compound from Podocarpus nagi, preferentially inhibits JAK2/STAT3 signaling by allosterically interacting with the regulatory domain of JAK2 and induces apoptosis of cancer cells

摘要

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways,especially the JAK2/STAT3 pathway,play vital roles in the development of many malignancies.Overactivation of STAT3 promotes cancer cell survival and proliferation.Therefore,the JAK2/STAT3-signaling pathway has been considered a promising target for cancer therapy.In this study,we identified a natural compound 3-deoxy-2β,16-dihydroxynagilactone E (B6) from the traditional Chinese medicinal plant Podocarpus nagi as a potent inhibitor of STAT3 signaling.B6 preferentially inhibited the phosphorylation of STAT3 by interacting with and inactivating JAK2,the main upstream kinase of STAT3.B6 dose-dependently inhibited IL-6-induced STAT3 signaling with an IC50 of 0.2 μM.In contrast to other JAK2 inhibitors,B6 did not interact with the catalytic domain but instead with the FERM-SH2 domain of JAK2.This interaction was JAK-specific since B6 had little effect on other tyrosine kinases.Furthermore,B6 potently inhibited the growth and induced apoptosis of MDA-MB-231 and MDA-MB-468 breast cancer cells with overactivated STAT3.Taken together,our study uncovers a novel compound and a novel mechanism for the regulation of JAK2 and offers a new therapeutic approach for the treatment of cancers with overactivated JAK2/STAT3.