Published online Mar 21, 2025. doi: 10.3748/wjg.v31.i11.102848
Revised: January 17, 2025
Accepted: February 11, 2025
Published online: March 21, 2025
Processing time: 130 Days and 3.1 Hours
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 mecha
To investigate the effect of apatinib on the glycolysis of vascular endothelial cells (VECs).
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.
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.
Apatinib influences the glycolytic pathway in the VECs of HCC a through the PI3K/AKT/PFKFB3 signaling pathway.
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.