engleski

Acid ceramidase activity regulates the sensitivity of human colon cancer cells to oxaliplatin.

Colorectal cancer (CRC) represents the global public health burden being the third most commonly diagnosed malignancy and the fourth leading cause of cancer-related deaths worldwide. Oxaliplatin, a third-generation platinum compound, has shown high activity in patients with metastatic CRC when combined with 5-fluorouracil and leucovorin. However, despite initial sensitivity to oxaliplatin, most cancer cells ultimately acquire drug resistance. Acid ceramidase (AC), a lysosomal lipid hydrolase that catalyses the degradation of pro-apoptotic ceramide into sphingosine and free fatty acid, has been implicated in the progression and resistance to therapy in multiple cancer types. However, the role of AC in colon cancer pathogenesis and response to chemotherapy has been poorly addressed so far. In the present study, we have found that AC is constitutively expressed in five human colon cancer cell lines, among which HCT116 and SW480 cells derived from primary tumours have highest expression levels of AC, whereas SW620 cells derived from lymph node metastasis exhibit lowest AC expression. Importantly, inhibition of AC activity by the potent AC inhibitor carmofur potentiated cytostatic activity of oxaliplatin and augmented oxaliplatin-induced apoptosis in HCT116 cells. Further insights into the mechanism of enhanced sensitivity to oxaliplatin induced by the AC inhibition were provided by Western blot analyses revealing that co-treatment of oxaliplatin and carmofur significantly reduced the expression levels of β1 integrin and p-FAK in HCT116 cells in comparison with single-agent treatment with oxaliplatin, which was associated with the suppression of downstream pro-survival signalling mediated by AKT and NF-κB. We also detected a marked decline in the expression level of previously identified prognostic marker and therapeutic target in CRC, namely transglutaminase 2, in combination treatment relative to oxaliplatin. It was also interesting to note that oxaliplatin alone was able to reduce the expression level of AC in HCT116 cells. Altogether, our study suggests that AC modulates in vitro response of colon cancer cells to oxaliplatin and encourages further investigation into the possible use of AC inhibitors in combination with oxaliplatin to improve treatment outcomes in CRC.

Acid ceramidase, colon cancer, oxaliplatin

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