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

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.

• Authors: Qun Zhao, Yun Bi, Jing Zhong, Xiang Li, Jian Guo, Ying-Xiang Liu, Long-Rui Pan, Yan Tan, Zhang-Shuang Deng, Xian-Jun Yu
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 42 Issue 5 Pg. 791-800 (May 2021) ISSN: 1745-7254 [Electronic] United States
• PMID: 32868906 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• STAT3 Transcription Factor
• STAT3 protein, human
• Zearalenone
• curvularin

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use, toxicity)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy)
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Cell Proliferation (drug effects)
• Drug Screening Assays, Antitumor
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Mice, Inbred BALB C
• Mice, Nude
• STAT3 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
• Xenograft Model Antitumor Assays
• Zearalenone (analogs & derivatives, pharmacology, therapeutic use, toxicity)