2. Academic Validation
  3. Ropivacaine as a novel AKT1 specific inhibitor regulates the stemness of breast cancer

Ropivacaine as a novel AKT1 specific inhibitor regulates the stemness of breast cancer

  • J Exp Clin Cancer Res. 2024 Mar 25;43(1):90. doi: 10.1186/s13046-024-03016-9.
Lin Ding # 1,  Hui Jiang # 2,  Qiangwei Li # 3,  Qiushuang Li 1,  Tian-Tian Zhang 3,  Limeng Shang 1,  Bin Xie 3,  Yaling Zhu 1,  Keshuo Ding 4,  Xuanming Shi 5,  Tao Zhu 6 7 8,  Yong Zhu 9
Affiliations

Affiliations

  • 1 Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.
  • 2 Department of Anesthesiology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China.
  • 3 School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China.
  • 4 Department of Pathology, School of Basic Medicine, Anhui Medical University, Hefei, China.
  • 5 School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China. xuanming.shi@hotmail.com.
  • 6 Department of Oncology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China. zhut@ustc.edu.cn.
  • 7 Key Laboratory of Immune Response and Immunotherapy, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China. zhut@ustc.edu.cn.
  • 8 Shenzhen Bay Laboratory, Shenzhen, 518055, China. zhut@ustc.edu.cn.
  • 9 Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China. zywp0508@ahmu.edu.cn.
  • # Contributed equally.
PMID: 38523299 DOI: 10.1186/s13046-024-03016-9
Abstract

Background: Ropivacaine, a local anesthetic, exhibits anti-tumor effects in various Cancer types. However, its specific functions and the molecular mechanisms involved in breast Cancer cell stemness remain elusive.

Methods: The effects of ropivacaine on breast Cancer stemness were investigated by in vitro and in vivo assays (i.e., FACs, MTT assay, mammosphere formation assay, transwell assays, western blot, and xenograft model). RNA-seq, bioinformatics analysis, Western blot, Luciferase reporter assay, and CHIP assay were used to explore the mechanistic roles of ropivacaine subsequently.

Results: Our study showed that ropivacaine remarkably suppressed stem cells-like properties of breast Cancer cells both in vitro and in vivo. RNA-seq analysis identified GGT1 as the downstream target gene responding to ropivacaine. High GGT1 levels are positively associated with a poor prognosis in breast Cancer. Ropivacaine inhibited GGT1 expression by interacting with the catalytic domain of Akt1 directly to impair its kinase activity with resultant inactivation of NF-κB. Interestingly, NF-κB can bind to the promoter region of GGT1. KEGG and GSEA analysis indicated silence of GGT1 inhibited activation of NF-κB signaling pathway. Depletion of GGT1 diminished stem phenotypes of breast Cancer cells, indicating the formation of NF-κB /Akt1/GGT1/NF-κB positive feedback loop in the regulation of ropivacaine-repressed stemness in breast Cancer cells.

Conclusion: Our finding revealed that local anesthetic ropivacaine attenuated breast Cancer stemness through Akt1/GGT1/NF-κB signaling pathway, suggesting the potential clinical value of ropivacaine in breast Cancer treatment.

Keywords

Breast cancer; Cancer stem cell; GGT1; NF-κB signaling pathway; Ropivacaine.

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