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

Abstract

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 IC 50 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.

High JAK2 Protein Expression Predicts a Poor Prognosis in Patients with Resectable Pancreatic Ductal Adenocarcinoma

“…Activated JAK2 phosphorylates STAT3, leading to its nuclear translocation and tumorigenesis [ 35 ]. A recent study showed that the natural compound B6 (3-deoxy-2 β ,16-dihydroxynagilactone E) inhibits the phosphorylation of STAT3 by inactivating and interacting with JAK2, thereby inhibiting growth and inducing apoptosis of breast cancer cells with overactivated STAT3; this provides a novel promising strategy for the treatment of cancers with JAK2/STAT3 overactivation [ 36 ]. A Japanese study found that p-STAT3 expression was correlated with OS, and the activation of the JAK2/STAT3 pathway is critical for the survival of clear-cell ovarian cancers [ 37 ].…”

Anticancer Activities and Mechanism of Action of Nagilactones, a Group of Terpenoid Lactones Isolated from Podocarpus Species

“…Interestingly, this compound does not classically bind to the kinase pocket of the enzyme, as it is frequently the case with small molecule inhibitors, but it was found to interact with the noncatalytic FERM-SH2 domain of JAK2. In doing so, B6 preferentially inhibits the growth of cancer cells with overactivated STAT3, like the MDA-MB-231 and MDA-MB-468 breast cancer cell lines, both potently engaged toward apoptosis under treatment with the Nag-E derivative [31].…”

“…The derivative 3-deoxy-2β-hydroxy-nagilactone E (Fig. 4 ) is also a potent inhibitor of cancer cell growth, 3-to-8-fold more active than its derivative 3-deoxy-2β,16-dihydroxy-nagilactone E (designated B6, [ 31 ]) against different cancer cell lines, and much more potent than its glycoside derivative 16-O-β- d -glucopyranosyl-nagilactone E which is totally inactive in vitro [ 15 ]. Preliminary structure–activity relationships can be defined in the Nag-E series.…”

“…The Nag-E derivative designated B6 (3-deoxy-2β,16-dihydroxy-nagilactone E) has been shown to inhibit the Janus kinase 2 enzyme (JAK2) [ 31 ]. It potently inhibits IL-6-induced phosphorylation of JAK2 and thus reduces the phosphorylation of the transcription factor STAT3 which is phosphorylated by JAK2.…”

Biological Evaluation of a New Brassinosteroid: Antiproliferative Effects and Targeting Estrogen Receptor α Pathways

“…It was found that phosphorylated STAT3 expression is associated with survival and mammographic density of breast cancer patients . Moreover, various natural compounds, including 3‐deoxy‐2 β ,16‐dihydroxynagilactone E, apigenin, genistein, inhibit STAT3 signaling and induce apoptosis in cancer cells . Therefore, proteins in pathways that are altered during the process of mammary tumorigenesis may be promising targets of future chemopreventive drugs .…”