Enhanced De Novo Lipid Synthesis Mediated by FASN Induces Chemoresistance in Colorectal Cancer

SIMPLE SUMMARY: Resistance to oxaliplatin threatens the prognosis in of colorectal cancer (CRC). As previous studies have aroused interest in fatty acid metabolism in cancer, we determined whether fatty acid biosynthesis contribute to oxaliplatin resistance in CRC. By leveraging the GEO databases, FASN gene signatures was correlated with the response to oxaliplatin-based chemotherapy and poor prognosis. Additionally, FASN expression was positively related with oxaliplatin resistance in vitro. Then, Orlistat, a typical FASN inhibitor, was applied to attenuate the resistance to oxaliplatin in cell culture and xenograft models. Additionally, the combination of the FASN inhibitor and oxaliplatin significantly increased cell cycle arrest and facilitated apoptosis, partly due to the diminished phosphorylation of the MAPK/ERK and PI3K/AKT pathways. Our study revealed that FASN enhanced resistance to oxaliplatin in CRC. Inhibition of FASN could rescue the response to oxaliplatin by regulating MAPK/ERK and PI3K/AKT pathways. ABSTRACT: Background: Oxaliplatin is one of the most widely used chemotherapy drugs for colorectal cancer (CRC). Resistance to oxaliplatin threatens the prognosis of CRC. Since previous studies have aroused interest in fatty acid metabolism in cancer, in this study, we determined whether fatty acid biosynthesis and the related regulating mechanism contribute to oxaliplatin resistance in CRC. Methods: The effect of the fatty acid synthase (FASN) and its inhibitor Orlistat was characterized in Gene Expression Omnibus (GEO) databases, oxaliplatin-resistant cell lines, and xenografts. MRNA-seq and analysis identified related pathway changes after the application of Orlistat, which was verified by Western blotting. Results: By leveraging the GEO databases, FASN and closely related gene signatures were identified as being correlated with the response to oxaliplatin-based chemotherapy and poor prognosis. Additionally, FASN-upregulated expression promoted oxaliplatin resistance in CRC cell lines. We then applied Orlistat, a typical FASN inhibitor, in cell culture and xenograft models of oxaliplatin-resistant CRC, which attenuated the resistance to oxaliplatin. Additionally, the combination of the FASN inhibitor and oxaliplatin significantly increased cell cycle arrest and facilitated apoptosis, partly due to the diminished phosphorylation of the MAPK/ERK and PI3K/AKT pathways. In vivo studies showed that inhibiting fatty acid biosynthesis with Orlistat restrained the growth of xenograft tumors and increased the responsiveness to oxaliplatin. Conclusions: Our study revealed that FASN enhanced resistance to oxaliplatin in CRC. The inhibition of FASN could rescue the response to oxaliplatin by regulating MAPK/ERK and PI3K/AKT pathways.