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.
Hubei Key Laboratory of Natural Products Research and Development, China Three Gorges University, Yichang, 443002, China.
Acta Pharmacol Sin. 2021 May;42(5):791-800. doi: 10.1038/s41401-020-0499-y. Epub 2020 Aug 31.
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·d, 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.
信号转导子和转录激活子 3（STAT3）的异常激活在许多类型的癌症中起着关键作用。因此，STAT3 已被确定为癌症治疗的潜在靶点。在这项研究中，我们鉴定出 10,11-去氢卷曲霉素（DCV），一种源自海洋真菌的天然产物大环内酯，为选择性 STAT3 抑制剂。我们表明，DCV（2-8 μM）剂量依赖性地抑制人乳腺癌细胞系 MDA-MB-231 和 MDA-MB-468 的增殖、迁移和侵袭，并诱导细胞凋亡。在这两种乳腺癌细胞系中，DCV 选择性抑制 STAT3 Tyr-705 的磷酸化，但不影响上游组件 JAK1 和 JAK2 以及 STAT3 的去磷酸化。此外，DCV 处理强烈抑制 IFN-γ 诱导的 STAT3 磷酸化，但对两种乳腺癌细胞系中 IFN-γ 诱导的 STAT1 和 STAT5 磷酸化没有显著影响。我们证明 DCV 的α，β-不饱和羰基部分对于 STAT3 失活至关重要。细胞热转移分析（CETSA）进一步揭示了 DCV 与 STAT3 的直接结合。在携带乳腺癌细胞系 MDA-MB-231 异种移植物的裸鼠中，用 DCV（30mg·kg·d，ip，14 天）治疗通过抑制 STAT3 激活显著抑制肿瘤生长，而没有观察到毒性。我们的研究结果表明，DCV 作为一种选择性 STAT3 抑制剂，可用于乳腺癌干预。
