Glypican-3 Enhances Reprogramming of Glucose Metabolism in Liver Cancer Cells

Abstract

Glypican-3(GPC3) is a transmembrane protein which has been found to be frequently overexpressed on the surfaces of liver cancer (LC) cells, which contributes to both the growth and metastasis of LC cells. Recently, the expression of GPC3 has been reported to be inversely associated with glucose metabolism activity in LC patients, suggesting that GPC3 may play a role in the regulation of glucose metabolism in LC. However, the role of GPC3 in glucose metabolism reprogramming, as well as in LC cell growth and metastasis, is unknown. Here, we found that GPC3 significantly contributed to the reprogramming of glucose metabolism in LC cells. On the one hand, GPC3 enhanced the glycolysis of LC cells through upregulation of the glycolytic genes of Glut1, HK2, and LDH-A. On the other hand, GPC3 repressed mitochondrial respiration through downregulation of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α), which has been well known as a crucial regulator in mitochondrial biogenesis. Mechanistic investigations revealed that HIF-1α was involved in both GPC3-regulated upregulation of glycolytic genes of HK2, PKM2, and Glut1 and downregulation of mitochondrial biogenesis regulator PGC-1α in LC cells. Additionally, GPC3-regulated reprogramming of glucose metabolism played a critical role in the growth and metastasis of LC cells. Conclusion. Our findings demonstrate that GPC3 is a critical regulator of glucose metabolism reprogramming in LC cells, which provides a strong line of evidence for GPC3 as an important therapeutic target to normalize glucose metabolic aberrations responsible for LC progression.

Development of an Aerobic Glycolysis Index for Predicting the Sorafenib Sensitivity and Prognosis of Hepatocellular Carcinoma

“…More importantly, aerobic glycolysis is related to multiple key cell signaling pathways, including PI3K/Akt, mTOR, and AMPK, and tightly associated with various cellular activities, including cell proliferation and EMT. In our study, the AGI was derived from a model consisting of genes encoding glucose transporters (SLC2A1, SLC2A2), key enzymes of glucose metabolism (G6PD, LDHA), and several other genes related to glycolysis (GPC1, HMMR, PLOD2, GOT2, STC2) (48)(49)(50)(51)(52)(53)(54), thereby supporting the use of the AGI as a marker of aerobic glycolysis activity. Several important genes related to glucose metabolism including HK2, PFK, and PKM2 are missed in the model of AGI, which had been reported to be associated with poor prognosis of HCC (55)(56)(57).…”

Glucose Metabolism and Oxidative Stress in Hepatocellular Carcinoma: Role and Possible Implications in Novel Therapeutic Strategies

“…GPC3 is involved in the reprogramming of tumor cell metabolism by acting on the glucose pathway ( Figure 1 ) [ 36 , 37 , 78 , 79 , 80 ]. HCC cells, in presence of high GPC3 protein expression, have a higher glucose uptake and lactate production [ 78 ]. GPC3 can enhance HIF-1α protein expression.…”

“…GPC3 can enhance HIF-1α protein expression. Knockdown of GPC3 expression was associated with tumor growth suppression, which was significantly reversed forcing the expression of HIF-1α [ 78 ]. A significant positive correlation was found between GPC3 expression and GLUT1, LDHA, and HK2 expression [ 78 ].…”

Prognostic significance of pyruvate kinase M2 expression in esophageal squamous cell carcinoma and its meta-analysis

“…Numerous oncological studies have focused on cancer metabolism due to the aberrant feature of energy production. Tumor cells acquire the vast majority of energy from glycolysis and lactic acid fermentation regardless of sufficient oxygen supply; this unique phenomenon is known as the Warburg effect, or aerobic glycolysis ( 4 ). Pyruvate kinase (PK) is one of the main rate-limiting enzymes in glycolysis.…”