The success of pharmacological treatments in primary liver cancers is limited by 
the marked efficacy of mechanisms of chemoresistance already present in 
hepatocytes. The role of the nuclear receptor FXR is unclear. Although, in 
non-treated liver tumors, its expression is reduced, the refractoriness to 
anticancer drugs is high. Moreover, the treatment with cisplatin up-regulates 
FXR. The aim of this study was to investigate whether FXR is involved in 
stimulating chemoprotection/chemoresistance in healthy and tumor liver cells. In 
human hepatocytes, the activation of FXR with the agonist GW4064 resulted in a 
significant protection against cisplatin-induced toxicity. In human hepatoma 
Alexander cells, with negligible endogenous expression of FXR, GW4064 also 
protected against cisplatin-induced toxicity, but only if they were previously 
transfected with FXR/RXR. Investigation of 109 genes potentially involved in 
chemoresistance revealed that only ABCB4, TCEA2, CCL14, CCL15 and KRT13 were 
up-regulated by FXR activation both in human hepatocytes and FXR/RXR-expressing 
hepatoma cells. In both models, cisplatin, even in the absence of FXR agonists, 
such as bile acids and GW4064, was able to up-regulate FXR targets genes, which 
was due to FXR-mediated trans-activation of response elements in the promoter 
region. FXR-dependent chemoprotection was also efficient against other 
DNA-damaging compounds, such as doxorubicin, mitomycin C and potassium 
dichromate, but not against non-genotoxic drugs, such as colchicine, paclitaxel, 
acetaminophen, artesunate and sorafenib. In conclusion, ligand-dependent and 
independent activation of FXR stimulates mechanisms able to enhance the 
chemoprotection of hepatocytes against genotoxic compounds and to reduce the 
response of liver tumor cells to certain pharmacological treatments.