By preferentially expressing isomers of glucose transporters, such as glucose transporter (GLUT) 1, key enzymes, such as hexokinase 2, and pyruvate kinase M2 (PKM2), cancer cells modulate and hijack the whole process of glucose metabolism to balance their inefficient glucose utilization, aerobic glycolysis (also known as Warburg effect), and high anabolic demands 4, 5. Among all the metabolic alterations, accelerated glucose metabolism may be the best-recognized example. Metabolic reprograming, one of the hallmarks of cancer, describes changes in uptake and utilization of different nutrients by cancer cells to attain high growth and proliferation rates 4. Therefore, novel treatments to improve outcomes of HCC patients are sorely needed. Sorafenib and regorafenib are currently approved for patients with advanced HCC 2, 3, but the response rate and the actual survival improvement to all of above-mentioned treatments are limited. The vast number of etiologies involved in tumor formation leads to a huge diversity of molecular signatures in HCC patients and poses a major challenge in successful treatment. Hepatocellular carcinoma (HCC), one of the most fatal human malignant diseases worldwide, is characterized by complex and heterogeneous factors 1. Our study highlights the unique dual β-catenin-inhibition mechanisms of CANA, which may provide new thoughts on treating HCC patient with concurrent diabetes, and, furthermore, on developing novel treatment targeting metabolic reprogram and/or WNT/β-catenin signaling in HCC. Moreover, using Huh7 xenografted tumor model, CANA treatment was shown to delay tumor growth and improved the survival of HCC bearing mice.
By co-treating cells with cycloheximide and MG-132, we proved that CANA promoted proteasomal degradation of β-catenin protein by increasing phosphorylation of β-catenin, and CANA-induced inactivation of protein phosphatase 2A was identified being responsible for this effect. Notably, we found that CANA treatment significantly downregulated the expression of β-catenin in HCC cells in. Canagliflozin (CANA), phloretin, and WZB117 decreased cellular glucose influx, but only CANA showed potent growth inhibition in HCC, which indicated a glucose-independent anti-HCC mechanism. In this study, we examined a collection of glucose transporter inhibitors and found differential anti-HCC effects among these compounds. Accelerated glucose metabolism is critical in hepatocarcinogenesis, but the utilities of different glucose transporter inhibitors in treating hepatocellular carcinoma (HCC) remain largely uncharacterized.
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