Celastrol delays hepatic steatosis and carcinogenesis in a rapid AKT/c-Met-transfected hepatocellular carcinoma model via suppressing fatty acid synthase expression and AKT/ERK phosphorylation

Although the suppressing effects of celastrol on hepatocellular carcinoma (HCC) have been demonstrated, evidence for the targeting of fatty acid synthetase (FASN) in the development of HCC by celastrol is still rare. In this study, the effect of celastrol on a rapid HCC model featuring co-activation of AKT/c-Met oncogenes in mice was studied. The effect of celastrol on the alpha-fetoprotein level in the liver and serum was also investigated. Protein expressions of PCNA, Ki67 and FASN in celastrol-treated AKT/c-Met HCC mice were observed. The molecular mechanism of celastrol on the AKT/c-Met signaling pathway was elucidated. The results revealed that celastrol significantly repressed the AKT/c-Met induced HCC development and down-regulated the mRNA expression of AFP in the liver and the AFP level in serum. Furthermore, the expression of proliferation-associated proteins in the HCC tissues was reduced by celastrol treatment. Moreover, the abundant steatosis that resulted from FASN accumulation in the liver in AKT/c-Met mice was also attenuated. Finally, the phosphorylation of AKT and ERK1/2 in HCC mice was repressed by celastrol treatment. Overall, our data demonstrate that celastrol exerts an antiproliferative and novel lipid-decreasing effect by targeting AKT/ERK and FASN in HCC development in vivo.