1. Academic Validation
  2. 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

  • J Transl Med. 2023 Aug 18;21(1):553. doi: 10.1186/s12967-023-04396-w.
Jie Lei # 1 Yujia Pan # 2 Rui Gao # 3 Bin He 1 Zifeng Wang 1 Xinxing Lei 1 Zijian Zhang 1 Na Yang 4 Min Yan 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncology in South China, Cancer Center, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University, Guangzhou, 510060, China.
  • 2 Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116023, China.
  • 3 Department of Medical Oncology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 510275, China.
  • 4 Department of Laboratory Medicine, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, 510180, China. eyyangna@scut.edu.cn.
  • 5 State Key Laboratory of Oncology in South China, Cancer Center, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University, Guangzhou, 510060, China. yanmin@sysucc.org.cn.
  • # Contributed equally.
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: Our results provide a platform for differentiation therapy drug discovery using 3D culture models and identify rutaecarpine as a potential compound for TNBC treatment.

Keywords

3D morphological screening; Differentiation therapy; Rutaecarpine.

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