The Mechanism Of Inhibition Of Insulin-induced PI3K/AKT Signal Pathway By Tumor Suppressor HBP21

Liver cancer is the sixth most common malignant tumor in the world and the fourth leading cause of cancer-related deaths in the world.It is generally believed that the occurrence of liver cancer is related to chronic hepatitis B virus and hepatitis C virus infection,alcoholism or dietary exposure to aflatoxin.The pathogenesis of liver cancer needs to be further elucidated.The role of insulin and its receptor in tumorigenesis is sup ported by clinical evidences.After insulin binds to its receptor(IRβ),IRβ can be phosphorylated and activated,thus activating downstream related molecules such as PI3 K,AKT and mTOR.Heat shock protein binding protein HBP21,a tumor suppressor gene,can promote tumor cell apoptosis.It is unclear whether HBP21 regulates abnormal activated PI3K/AKT signal pathway in tumor cells.In the study,we found that HBP21 was lowly expressed in liver cancer tissues.Overexpression of HBP21 in hepatome cell line Huh7 significantly inhibited the phosphorylation of AKT and mTOR in insulin-activated PI3K/AKT signal pathway while it did not affect the ubiquitin of AKT and the protein level of PTEN.Further studies showed that HBP21 inhibited the phosphorylation of IRβ triggered by insulin.All the data suggest that HBP21 may inhibit the phosphorylation of AKT and mTOR by suppressing the phosphorylation of insulin receptor IRβ,thus blocking the activation of insulin-induced PI3K/AKT/mTOR signal pathway.We explain how HBP21 inhibits the activation of PI3K/AKT signal pathway by insulin and enriches its function as a tumor suppressor.The depressed expression of HBP21 in hepatocellular carcinoma and its inhibition of insulin/PI3K/AKT activation make it a potential target for cancer therapy.