Rutaecarpine induces the differentiation of triple-negative breast cancer cells through inhibiting fumarate hydratase.
Rutaecarpine induces the differentiation of triple-negative breast cancer cells through inhibiting fumarate hydratase.
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DOI：
10.1186/s12967-023-04396-w
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发表时间：
2023-08-18
影响因子：
7.4
通讯作者：
Yan, Min
中科院分区：
文献类型：
--
作者：
Lei, Jie;Pan, Yujia;Gao, Rui;He, Bin;Wang, Zifeng;Lei, Xinxing;Zhang, Zijian;Yang, Na;Yan, Min
三阴性乳腺癌（TNBC）是最具侵袭性的人类癌症之一，预后不良。大约80%的TNBC病例属于分子基底样亚型，其可以通过诱导分化来治疗性地利用。然而，用于诱导TNBC分化的策略仍然未被探索。使用基于天然化合物文库的三维（3D）形态学筛选模型来鉴定可以诱导TNBC细胞分化的可能的候选化合物。采用RT-qPCR、RNA-seq、流式细胞术、免疫荧光、SCENITH和无标记LC-MS/MS等方法验证了吴茱萸次碱的疗效。通过药物亲和反应靶点稳定性（DARTS）试验鉴定了吴茱萸次碱的直接靶点。还构建了异种移植小鼠模型以证实吴茱萸次碱的体内作用。我们鉴定了吴茱萸次碱，一种吲哚并吡啶并喹唑啉酮，在3D球状体和体内小鼠模型中诱导基底TNBC细胞的管腔分化。从机制上讲，吴茱萸次碱处理导致3D培养的TNBC细胞中的整体代谢应激和升高的ROS。此外，NAC，一种ROS的清除剂，在3D培养中阻碍了吴茱萸次碱诱导的TNBC细胞的分化。最后，我们确定延胡索酸水合酶（FH）作为吴茱萸次碱的直接相互作用的目标。FH的抑制和FH的敲低一致地诱导3D培养中的TNBC细胞的分化。我们的研究结果提供了一个平台，分化治疗药物发现使用三维培养模型，并确定吴茱萸次碱作为一个潜在的化合物TNBC治疗。在线版本包含补充材料，可通过10.1186/s12967-023-04396-w获得。
Triple-negative breast cancer (TNBC) is one of the most aggressive human cancers and has poor prognosis. Approximately 80% of TNBC cases belong to the molecular basal-like subtype, which can be exploited therapeutically by inducing differentiation. However, the strategies for inducing the differentiation of TNBC remain underexplored. A three-dimensional (3D) morphological screening model based on a natural compound library was used to identify possible candidate compounds that can induce TNBC cell differentiation. The efficacy of rutaecarpine was verified using assays: RT-qPCR, RNA-seq, flow cytometry, immunofluorescence, SCENITH and label-free LC–MS/MS. The direct targets of rutaecarpine were identified through drug affinity responsive target stability (DARTS) assay. A xenograft mice model was also constructed to confirm the effect of rutaecarpine in vivo. We identified that rutaecarpine, an indolopyridoquinazolinone, induces luminal differentiation of basal TNBC cells in both 3D spheroids and in vivo mice models. Mechanistically, rutaecarpine treatment leads to global metabolic stress and elevated ROS in 3D cultured TNBC cells. Moreover, NAC, a scavenger of ROS, impedes rutaecarpine-induced differentiation of TNBC cells in 3D culture. Finally, we identified fumarate hydratase (FH) as the direct interacting target of rutaecarpine. The inhibition of FH and the knockdown of FH consistently induced the differentiation of TNBC cells in 3D culture. Our results provide a platform for differentiation therapy drug discovery using 3D culture models and identify rutaecarpine as a potential compound for TNBC treatment. The online version contains supplementary material available at 10.1186/s12967-023-04396-w.
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