Gitogenin Impedes Tumorigenesis in Hepatocellular Carcinoma via NUAK2/NF-κB Axis

Abstract

Hepatocellular carcinoma (HCC) is a common malignant primary liver cancer, with the high incidence rate and lethality in China. Gitogenin (Gito), as a saponin composition in traditional Chinese medicine, which exhibits a notable pharmacological activity to enhance blood circulation and improve cerebral ischemia. However, it remains a blank to identify the anti-HCC activity of Gito and its potential mechanism. In vitro and In vivo studies including MTT, colony formation, immunofluorescence (IF) staining, Western blot, wound healing assay, Transwell assay, and PDX models, etc. were applied to assess the anti-HCC activity of Gito. In vitro and in vivo studies including Western blot, wound healing, Transwell, and PDX models, IF staining, etc. were utilized to evaluate the potential mechanism of Gito in treating HCC. Gito inhibited the growth and development of HCC cells/mice by inducing autophagic and metastatic activities through the NUAK2/NF-κB axis. Gito acted as a promising inhibitor of NUAK2. In PDX tumors, Gito showed potential therapeutic effects by binding NUAK2. Our study provides a scientific basis for the first time for Gito regulating HCC cells autophagic, EMT, and metastatic ability through the NUAK2/NFκB axis, which may be recognized as a prospective drug candidate for the therapy of HCC patients.

Funding: This work was supported by grants from the Natural Science Foundation of Tianjin Municipality (No. 23JCJQJC00040), Natural Science Foundation of Tianjin Municipality (No. 23JCZXJC00150), National Natural Science Foundation of China (No. 82274154), Science and Technology Project of Haihe Laboratory of Modern Chinese Medicine (No. 22HHZYSS00008), and Natural Science Foundation of Inner Mongolia Autonomous Region of China (No. 2023MS08043).

Declaration of Interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethical Approval: The study was approved by the committee, and patients signed the informed consent. All procedures were conducted by the Animal Use and Care Committee of Tianjin University of Traditional Chinese Medicine (Permit number: TCM-LAEC2019099).

Keywords: hepatocellular carcinoma, autophagy, EMT, Gito, NUAK2