| Liver cancer most commonly develops in patients with chronic liver disease,the etiology of which includes viral hepatitis(B and C),alcohol,obesity,dietary carcinogens,and so forth.The current treatment modalities,including surgical resection and liver transplantation,have been found far from effective.FC belongs to diosgenin compounds.Preclinical studies have shown a good anti-hepatoma activity,but its specific anti-hepatoma mechanism is not clear.Signal transducers and transcriptional activators 3(STAT3)is often discovered in many cancer types.Overexpression of STAT3 is particularly associated with low survival in patients with hepatocellular carcinoma.This study discussed the mechanism of FC based on STAT3 protein on hepatocellular carcinoma.Our results showed that FC with 3 rhamnosyls had the best antitumor activity among DGR-1,dioscin,FC and DGR-4 and target STAT3.By molecular docking,FC and STAT3 have the best binding ability.Firstly,MTT test showed that FC had the best antitumor activity on HepG2,Over-HepG2 and Knock-HepG2 cell lines among the above compounds.All these showed that the cytotoxicity of diosgenin compounds was positively correlated with the level of STAT3 in cancer cells.At the same time,we found that hypoxia did not lead to diosgenyl saponins resistance.The sensitivity of FC to Knock-HepG2 cells was 65% higher than that of wild-type HepG2 cells.Meanwhile,endogenous metabolites in HepG2 cells were detected by GC/MS.As a result,FC reduced key products in gluconeogenic pathways both under hypoxia and normoxia,such as lactate,pyruvate and citrate.STAT3 from different organelles is involved in different biological events.In this research,we examined the changes of STAT3 in nucleus,cytoplasm,mitochondria and total cellular proteins in HepG2 cells.We found that FC inhibited STAT3 and its phosphorylation in every organ,especial for the site of S727 in the mitochondria.Furthermore,HCC xenograft mouse model was used to verified the synergistic effect of sorafenib and FC.Combination of FC and sorafenib increased sorafenib sensitivity in HCC under hypoxia environment and in HCC xenograft mice.In conclusion,these results suggest that FC should be used as a STAT3 inhibitor,and FC can increase the sensitivity of HCC patients to sorafenib.These results provide a potential theoretical basis for the anti-hepatoma effect of FC. |
