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首頁> 美國衛(wèi)生研究院文獻>Biochemistry Insights >Withaferin A Inhibits STAT3 and Induces Tumor Cell Death in Neuroblastoma and Multiple Myeloma
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Withaferin A Inhibits STAT3 and Induces Tumor Cell Death in Neuroblastoma and Multiple Myeloma

機譯：Withaferin A抑制STAT3并誘導神經(jīng)母細胞瘤和多發(fā)性骨髓瘤的腫瘤細胞死亡

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Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor that has been implicated in many human cancers and has emerged as an ideal target for cancer therapy. Withaferin A (WFA) is a natural product with promising antiproliferative properties through its association with a number of molecular targets including STAT3. However, the effect of WFA in pediatric neuroblastoma (NB) and its interaction with STAT3 have not been reported. In this study, we found that WFA effectively induces dose-dependent cell death in high-risk and drug-resistant NB as well as multiple myeloma (MM) tumor cells, prevented interleukin-6 (IL-6)–mediated and persistently activated STAT3 phosphorylation at Y705, and blocked the transcriptional activity of STAT3. We further provide computational models that show that WFA binds STAT3 near the Y705 phospho-tyrosine residue of the STAT3 Src homology 2 (SH2) domain, suggesting that WFA prevents STAT3 dimer formation similar to BP-1-102, a well-established STAT3 inhibitor. Our findings propose that the antitumor activity of WFA is mediated at least in part through inhibition of STAT3 and provide a rationale for further drug development and clinical use in NB and MM.
機譯：信號轉(zhuǎn)導和轉(zhuǎn)錄激活因子3（STAT3）是一種致癌轉(zhuǎn)錄因子，已與許多人類癌癥有關，并已成為癌癥治療的理想靶標。 Withaferin A（WFA）是一種天然產(chǎn)品，通過與包括STAT3在內(nèi)的許多分子靶標相關聯(lián)，具有有希望的抗增殖特性。但是，尚未報道WFA在小兒神經(jīng)母細胞瘤（NB）中的作用及其與STAT3的相互作用。在這項研究中，我們發(fā)現(xiàn)WFA可有效誘導高風險和耐藥性NB以及多發(fā)性骨髓瘤（MM）腫瘤細胞中劑量依賴性細胞死亡，阻止白介素6（IL-6）介導并持續(xù)激活的STAT3在Y705處磷酸化，并阻斷STAT3的轉(zhuǎn)錄活性。我們進一步提供了計算模型，該模型顯示W(wǎng)FA結(jié)合STAT3 Src同源2（SH2）域的Y705磷酸酪氨酸殘基附近的STAT3，這表明WFA可以阻止STAT3二聚體的形成，類似于成熟的STAT3抑制劑BP-1-102 。我們的發(fā)現(xiàn)表明，WFA的抗腫瘤活性至少部分是通過抑制STAT3介導的，并為進一步開發(fā)藥物和在NB和MM中臨床應用提供了依據(jù)。

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