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10,11-dehydrocurvularin exerts antitumor effect against human breast cancer by suppressing STAT3 activation
Qun Zhao1, Yun Bi1, Jing Zhong1,2
1Laboratory 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.
Abstract:
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.
Insights
Marine fungus-derived 10,11-dehydrocurvularin (DCV) selectively inhibits signal transducer and activator of transcription 3 (STAT3) in breast cancer cells. DCV suppressed tumor growth in mice, offering a potential new cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Natural Products Chemistry
Background:
- Aberrant activation of signal transducer and activator of transcription 3 (STAT3) is implicated in numerous cancers, making it a key therapeutic target.
- Identifying novel, selective inhibitors of STAT3 is crucial for developing effective cancer treatments.
Purpose of the Study:
- To identify and characterize novel natural products as selective STAT3 inhibitors for cancer therapy.
- To evaluate the efficacy of 10,11-dehydrocurvularin (DCV) in preclinical models of breast cancer.
Main Methods:
- Screening of marine fungus-derived compounds to identify STAT3 inhibitors.
- In vitro assays using human breast cancer cell lines (MDA-MB-231, MDA-MB-468) to assess proliferation, migration, invasion, and apoptosis.
- Western blotting to analyze STAT3 phosphorylation and related signaling pathways.
- In vivo studies using nude mice xenograft models to evaluate tumor growth inhibition and toxicity.
- Cellular thermal shift assay (CETSA) to confirm direct target engagement.
Main Results:
- 10,11-dehydrocurvularin (DCV) was identified as a potent and selective inhibitor of STAT3.
- DCV dose-dependently inhibited proliferation, migration, and invasion while inducing apoptosis in breast cancer cells.
- DCV selectively inhibited STAT3 phosphorylation at Tyr-705 without affecting upstream JAK kinases or STAT3 dephosphorylation.
- DCV treatment suppressed tumor growth in vivo without observable toxicity, linked to STAT3 inhibition.
- The α, β-unsaturated carbonyl moiety of DCV was essential for its STAT3 inhibitory activity.
Conclusions:
- 10,11-dehydrocurvularin (DCV) is a novel, marine-derived natural product with selective STAT3 inhibitory activity.
- DCV demonstrates significant potential as a therapeutic agent for breast cancer intervention by targeting STAT3.
- Further investigation into DCV as a lead compound for cancer drug development is warranted.
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