AFP Stimulates Glucose Metabolic Reprogramming Contributing to Hepatocellular Carcinoma Resist Sorafenib Through Activating PI3K/AKT Signalling Pathway.

Alpha fetoprotein (AFP) regulates glucose metabolism reprogramming (GMR) related to drug resistance of hepatocellular carcinoma (HCC) and remains unclear. This study explores the effect of AFP regulating GMR (Glucose metabolic reprogramming) on the tolerance of HCC cells to sorafenib. Thirty clinical liver cancer samples and multi-omics databases were collected; the expression of AFP, GMR-related proteins, pyruvate kinase M2 (PKM2), and the PI3K/AKT signalling pathway-associated proteins were assessed using immunohistochemistry (IHC) or Western blotting. MTT, cloning assays, flow cytometry, and TUNEL were performed to evaluate the effects of AFP on HCC resistance to sorafenib. Alterations in glucose consumption, lactate dehydrogenase activity, and ATP production were measured. Co-immunoprecipitation and immunofluorescence experiments were conducted to determine how AFP interacts with PKM2. An in vivo mouse tumour model was used to investigate the restoration of tumorigenesis and development. The results indicated that AFP inhibited sorafenib-induced apoptosis of HCC cells. AFP activated the PI3K/AKT signalling pathway to promote the GMR-related protein expression and enzyme activity. Particularly, AFP's interaction with PKM2 stimulated the activity of PKM2 to enhance GMR, contributing to HCC resistance to sorafenib. In vivo experiments demonstrated that inhibition of AFP expression attenuated tumorigenesis and growth, and this effect was restored by overexpression of PKM2; PKM2 played a critical activated role in AFP mediating the GMR in HCC. In conclusion, AFP activates the PI3K/AKT signalling pathway to augment aerobic glycolysis in HCC cells, leading to HCC resistance to sorafenib. Inhibition of AFP expression and targeting of PKM2 may represent a novel approach for clinically reversing sorafenib tolerance in HCC patients.