Acid ceramidase inhibition sensitizes human colon cancer cells to oxaliplatin through downregulation of transglutaminase 2 and β1 integrin/FAK-mediated signalling.

Acid ceramidase (ASAH1) has been implicated in the progression and chemoresistance in different cancers. Its role in colon cancer biology and response to standard chemotherapy has been poorly addressed so far. Here, we have investigated ASAH1 expression at the protein level in human colon cancer cell lines and tissues from colon cancer patients, and have examined in vitro the possible link between ASAH1 expression and functional activity of p53 protein whose inactivation is associated with the progression from adenoma to malignant tumour in colon cancer. Finally, we have explored the role of ASAH1 in response and resistance mechanisms to oxaliplatin (OXA) in HCT 116 colon cancer cells. We have demonstrated that human colon cancer cells and colorectal adenocarcinoma tissues constitutively express ASAH1, and that its expression is higher in tumour tissues than in normal colonic mucosa. Furthermore, we found an inverse correlation between ASAH1 expression and p53 functional activity. Obtained data revealed that ASAH1 was involved in HCT 116 cell response to OXA and that anti-proliferative, pro-apoptotic, anti-migratory and anti-clonogenic effects of OXA could be significantly increased by combination treatment with ASAH1 inhibitor carmofur. Increased OXA sensitivity was associated with downregulation of signalling involved in acquired resistance to OXA in colon cancer, in particular transglutaminase 2 and β1 integrin/FAK, which resulted in the suppression of NF-κB and Akt. Thus, combination of OXA with ASAH1 inhibitors could be a promising strategy to counter chemoresistance and improve treatment outcome in advanced colon cancer.