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

• 作者: Qun Zhao Yun Bi Jing Zhong Xiang Li Jian Guo Ying-xiang Liu Long-rui Pan Yan Tan Zhang-shuang Deng Xian-jun Yu
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2021,（5）
• 所属期刊栏目: Chemotherapy
• 页码范围: 791-800
• 页数: 10页
• 语种: 英文

摘要

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) dosedependently inhibited the proliferation,migration and invasion of human breast cancer ceil lines MDA-MB-231 and MDA-M8-468,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-y-induced STAT3 phosphorylation but had no significant effect on IFN-y-induced STAT1 and STATS 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 DC/with STAT3.In nude mice bearing breast cancer cell line MDA-MB-231 xenografts,treatment with DC/(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.