Overexpression of sortilin is associated with 5‐FU resistance and poor prognosis in colorectal cancer

Colorectal cancer (CRC) is the third most common cancer worldwide. Even if 5‐fluorouracil (5‐FU) is used as the first‐line chemotherapeutic drug, responsiveness is only 20‐30%. Acquired resistance to 5‐FU contributes to both poor patient prognosis and relapse, emphasizing the need to identify biomarkers. Sortilin, a vacuolar protein sorting 10 protein (Vps10p), implicated in protein trafficking, is over expressed in CRC cell lines cultured 72 hours in presence of 5‐FU. This overexpression was also observed in 5‐FU‐resistant cells derived from these cell lines as well as in CRC primary cultures (or patients derived cell lines). A significantly higher expression of sortilin was observed in vivo, in 5‐FU‐treated tumours engrafted in Nude mice, as compared with non‐treated tumour. A study of transcriptional regulation allowed identifying a decrease in ATF3 expression, as an explanation of sortilin overexpression following 5‐FU treatment. In silico analysis revealed SORT1 expression correlation with poor prognosis. Moreover, sortilin expression was found to be positively correlated with CRC tumour grades. Collectively, our findings identify sortilin as a potential biomarker of 5‐FU resistance associated with poor clinical outcomes and aggressiveness in CRC. As a new prognostic factor, sortilin expression could be used to fight against CRC.