10,11-dehydrocurvularin exerts antitumor effect against human breast cancer by suppressing STAT3 activation

Aberrant activation of signal transducer and activator of transcription 3 (STAT3) plays a critical role in many types of cancers. As a result, STAT3 has been identified as a potential target for cancer therapy. In this study we identified 10,11-dehydrocurvularin (DCV), a natural-product macrolide derived from marine fungus, as a selective STAT3 inhibitor. We showed that DCV (2-8 mu M) dose-dependently inhibited the proliferation, migration and invasion of human breast cancer cell lines MDA-MB-231 and MDA-MB-468, and induced cell apoptosis. In the two breast cancer cell lines, DCV selectively inhibited the phosphorylation of STAT3 Tyr-705, but did not affect the upstream components JAK1 and JAK2, as well as dephosphorylation of STAT3. Furthermore, DCV treatment strongly inhibited IFN-gamma-induced STAT3 phosphorylation but had no significant effect on IFN-gamma-induced STAT1 and STAT5 phosphorylation in the two breast cancer cell lines. We demonstrated that the alpha, beta-unsaturated carbonyl moiety of DCV was essential for STAT3 inactivation. Cellular thermal shift assay (CETSA) further revealed the direct engagement of DCV with STAT3. In nude mice bearing breast cancer cell line MDA-MB-231 xenografts, treatment with DCV (30 mg center dot kg(-1)center dot d(-1), ip, for 14 days) markedly suppressed the tumor growth via inhibition of STAT3 activation without observed toxicity. Our results demonstrate that DCV acts as a selective STAT3 inhibitor for breast cancer intervention.

Automated summary

The study identified 10,11-dehydrocurvularin (DCV) as a selective inhibitor of STAT3 for intervention in breast cancer, demonstrating its ability to inhibit proliferation, migration, invasion, and induce apoptosis in breast cancer cell lines. DCV directly engages with STAT3 and inhibits its phosphorylation activity, leading to tumor growth inhibition without observed toxicity in mouse xenograft models.