Mechanism, Clinical Significance, and Treatment Strategy of Warburg Effect in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver and the third leading cause of cancer death worldwide. The incidence of HCC accounts for more than 90% of primary HCC. Like most solid malignancies, the occurrence and development of HCC are closely related to the Warburg effect. The Warburg effect of HCC is mainly manifested as increased glucose uptake by HCC cells, increased glycolysis, restricted mitochondrial oxidative phosphorylation, increased pentose phosphate pathway in HCC cells, and increased glutamine decomposition. As the contribution of glycolysis to the total ATP of tumor cells generally does not exceed 50% to 60%, oxidative phosphorylation (OXPHOS) still makes a considerable contribution to the ATP of tumor cells. In some cases, there will be an anti-Warburg effect. HCC Warburg effect is closely related to HCC cell proliferation, apoptosis, immune escape, migration and invasion, chemotherapy resistance, and treatment failure. The mechanism of the Warburg effect in HCC is complex, involving the expression of stimulating the key glycolysis enzymes by hypoxia-inducible factor-1(HIF-1), the activation of oncogenes and the inactivation of tumor suppressor genes, the continuous activation of related signaling pathways, the participation of noncoding RNA, and the rate of metabolism gene mutation of enzyme. This article synthetically discusses the characteristics of glucose metabolism in HCC cells, the mechanism of Warburg effect, clinical significance, and corresponding treatment strategies and provides new perspectives for the prevention and treatment of HCC.

Comprehensive Multi-Omic Analysis Reveals Distinct Molecular Features in Early and Advanced Stages of Hepatocellular Carcinoma

“…As mentioned earlier, proteome and metabolome changes are the downstream consequence of cell signaling, and the tumor tissue may already be in a low-glucose equilibrium if insufficient materials are supplied. Additionally, the traditional Warburg effect has been increasingly challenged due to different cancer types and diverse tumor microenvironments, and these phenomena might also be caused by tumor stromal cells, resulting in the observation of a reverse Warburg effect [51][52][53]. Moreover, glutamate was significantly increased in advanced-stage HCC, indicating the activation of an alternative energy generation pathway.…”

The expression of cuproptosis-related genes in hepatocellular carcinoma and their relationships with prognosis

“…Copper depletion in mitochondria switches cellular metabolism from cellular respiration to glycolysis (50). The Warburg effect in HCC is mainly characterized by increased glucose uptake, elevated glycolysis, restricted mitochondrial OXPHOS, heightened glutamine catabolism, and enhanced pentose phosphate pathway in HCC cells, and is closely associated with HCC cell proliferation, migration, invasion, apoptosis, immune escape, chemotherapy suppression and treatment failure (51). Thus, the role of copper in hepatocarcinogenesis indicated that cuproptosis may be intimately associated with alleviation of mitochondrial dysfunction and reduction of glycolysis in HCC patients, providing an idea into the discovery of novel therapies related to cuproptosis for liver cancer.…”

Metabolic reprogramming and its clinical implication for liver cancer

“…[97] BAY-876 is a Glut1 antagonist, and single injection of microcrystalline BAY-876 into HCC tumor tissues led to inhibition of glucose uptake, proliferation, and epithelial-to-mesenchymal transition of HCC in mice. [191] Liu et al [152] reported that aspirin reduced glucose uptake and hepatoma proliferation in vitro and in mice by downregulating Glut1. Everolimus is a mTOR inhibitor, and it suppresses glucose uptake and tumor angiogenesis by reducing HIF-1α expression (Table 1).…”

“…For example, downregulating Glut1 expression by long non-coding RNA (lncRNA) SLC2A1-AS1 suppressed the proliferation and metastasis of HCC, 190 and targeting Glut1 by siRNA suppressed CCA cell migration and invasion 97 . BAY-876 is a Glut1 antagonist, and single injection of microcrystalline BAY-876 into HCC tumor tissues led to inhibition of glucose uptake, proliferation, and epithelial-to-mesenchymal transition of HCC in mice 191 . Liu et al 152 reported that aspirin reduced glucose uptake and hepatoma proliferation in vitro and in mice by downregulating Glut1.…”