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

Qun Zhao1, Yun Bi1, Jing Zhong1,2, Xiang Li1, Jian Guo1, Ying-xiang Liu1, Long-rui Pan1, Yan Tan1, Zhang-shuang Deng2, Xian-jun Yu1
1 Laboratory of Inflammation and Molecular Pharmacology, School of Basic Medical Sciences & Biomedical Research Institute, Hubei University of Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan 442000, China
2 Hubei Key Laboratory of Natural Products Research and Development, China Three Gorges University, Yichang 443002, China
Correspondence to: Zhang-shuang Deng:, Xian-jun Yu:,
DOI: 10.1038/s41401-020-0499-y
Received: 8 March 2020
Accepted: 29 June 2020
Advance online: 31 August 2020


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 μM) 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-γ-induced STAT3 phosphorylation but had no significant effect on IFN-γ-induced STAT1 and STAT5 phosphorylation in the two breast cancer cell lines. We demonstrated that the α, β-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·kg−1·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.
Keywords: breast cancer; STAT3; 10 11-dehydrocurvularin; cellular thermal shift assay; MDA-MB-231 cells; MDA-MB-468 cells; tumor growth

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