Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 21, 2025; 31(11): 102848
Published online Mar 21, 2025. doi: 10.3748/wjg.v31.i11.102848
Apatinib regulates the glycolysis of vascular endothelial cells through PI3K/AKT/PFKFB3 pathway in hepatocellular carcinoma
Yi Wu, Bin-Bin Xie, Bing-Liang Zhang, Qing-Xin Zhuang, Shi-Wei Liu, Hong-Ming Pan
Yi Wu, Bin-Bin Xie, Hong-Ming Pan, Division of Cancer Medicine, Sir Run Run Shaw Medical Center, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
Bing-Liang Zhang, Qing-Xin Zhuang, Shi-Wei Liu, Section of Oncology, Ningxia Hui Autonomous Region General Hospital, Ningxia Medical University, Yinchuan 750000, Ningxia Hui Autonomous Region, China
Author contributions: Xie BB and Pan HM designed the research study; Wu Y, Zhang BL, Zhuang QX, and Liu SW performed the research.
Supported by the National Natural Science Foundation of China, No. 82100542 and No. 81802842.
Institutional review board statement: The study was reviewed and approved by the Run Run Shaw Hospital, Zhejiang University Institutional Review Board, No. 20201113-30.
Institutional animal care and use committee statement: All animal experiments were performed in accordance with the protocols approved by the Animal Care and Use Committee of Zhejiang University. No. SRRSH202302100.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: All data generated or analyzed in this study are included in the published article. The dataset used or analyzed in this study can be obtained from the corresponding author upon reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Hong-Ming Pan, Division of Cancer Medicine, Sir Run Run Shaw Medical Center, Zhejiang University School of Medicine, No. 3 East Qinchun Road, Hangzhou 310016, Zhejiang Province, China. panhongming@zju.edu.cn
Received: November 11, 2024
Revised: January 17, 2025
Accepted: February 11, 2025
Published online: March 21, 2025
Processing time: 130 Days and 3.1 Hours
Abstract
BACKGROUND

Hepatocellular carcinoma (HCC) is a prevalent and aggressive malignancy in the Chinese population; the severe vascularization by the tumor makes it difficult to cure. The high incidence and poor survival rates of this disease indicate the search for new therapeutic alternatives. Apatinib became a drug of choice because it inhibits tyrosine kinase activity, mainly through an effect on vascular endothelial growth factor receptor-2, thereby preventing tumor angiogenesis. This mechanism of action makes apatinib effective in the treatment of HCC.

AIM

To investigate the effect of apatinib on the glycolysis of vascular endothelial cells (VECs).

METHODS

This present study has investigated the effects of HCC cells on VECs, paying particular attention to changes in the glycolytic activity of VECs. The co-culture system established in the present study examined key cellular functions such as extracellular acidification rate and oxygen consumption rate. It also discusses participation of apatinib in the above processes. Core to the findings is the phosphatidylinositol 3-kinase (PI3K)/AKT/6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) signaling pathway, emphasizing the function of phosphorylated AKT and its interaction with PFKFB3, an essential regulator of glycolysis. In the investigation, molecular mechanisms by which such a pathway could influence the above VECs functions of proliferation, migration, and tube formation were underlined through coimmunoprecipitation analysis. Besides, supplementary in vivo experiments on nude mice provided additional biological relevance to the obtained results.

RESULTS

The glycolytic metabolism in VECs co-cultured with HCC cells is highly active, and the increased glycolysis in these endothelial cells accelerates the malignant transformation of HCC cells. Apatinib has been shown to inhibit this glycolytic activity in the VECs. It also hinders the development, multiplication, and movement of these cells while encouraging their programmed cell death. Moreover, biological analysis revealed that apatinib mainly influences VECs by regulating the PI3K/AKT signaling pathway. Subsequent research indicated that apatinib blocks the PI3K/AKT/PFKEB3 pathway, which in turn reduces glycolysis in these cells.

CONCLUSION

Apatinib influences the glycolytic pathway in the VECs of HCC a through the PI3K/AKT/PFKFB3 signaling pathway.

Keywords: Apatinib; Hepatocellular carcinoma; Vascular endothelial cells; Glycolysis; Phosphatidylinositol 3-kinase; Protein kinase B; 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3

Core Tip: Hepatocellular carcinoma (HCC) is characterized by its rich vascularization and highly active metabolic processes. As a vascular endothelial growth factor receptor-2-targeting agent, apatinib serves as a primary therapeutic option for HCC patients. Nevertheless, the impact of apatinib on the metabolic activities of vascular endothelial cells remains poorly understood. The study revealed that apatinib modulates glycolysis in HCC-associated vascular endothelial cells through the phosphatidylinositol 3-kinase/AKT/6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 signaling cascade. These findings provide insights into the molecular mechanism of apatinib’s action on endothelial cells and uncover a potential therapeutic target for HCC patients with high 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 expression.