| Autor: |
Drury J; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA., Geisen ME; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA., Tessmann JW; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA., Rychahou PG; Department of Surgery, University of Kentucky, Lexington, KY 40536, USA.; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA., Kelson CO; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA., He D; Markey Cancer Center Biostatistics and Bioinformatics Shared Resource Facility, University of Kentucky, Lexington, KY 40536, USA., Wang C; Markey Cancer Center Biostatistics and Bioinformatics Shared Resource Facility, University of Kentucky, Lexington, KY 40536, USA., Evers BM; Department of Surgery, University of Kentucky, Lexington, KY 40536, USA.; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA., Zaytseva YY; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA.; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA. |
| Abstrakt: |
Fatty acid synthesis has been extensively investigated as a therapeutic target in cancers, including colorectal cancer (CRC). Fatty acid synthase (FASN), a key enzyme of de novo lipid synthesis, is significantly upregulated in CRC, and therapeutic approaches of targeting this enzyme are currently being tested in multiple clinical trials. However, the mechanisms behind the pro-oncogenic action of FASN are still not completely understood. Here, for the first time, we show that overexpression of FASN increases the expression of glutamine-fructose-6-phosphate transaminase 1 (GFPT1) and O-linked N-acetylglucosamine transferase (OGT), enzymes involved in hexosamine metabolism, and the level of O-GlcNAcylation in vitro and in vivo. Consistently, expression of FASN significantly correlates with expression of GFPT1 and OGT in human CRC tissues. shRNA-mediated downregulation of GFPT1 and OGT inhibits cellular proliferation and the level of protein O-GlcNAcylation in vitro, and knockdown of GFPT1 leads to a significant decrease in tumor growth and metastasis in vivo. Pharmacological inhibition of GFPT1 and OGT leads to significant inhibition of cellular proliferation and colony formation in CRC cells. In summary, our results show that overexpression of FASN increases the expression of GFPT1 and OGT as well as the level of protein O-GlcNAcylation to promote progression of CRC; targeting the hexosamine biosynthesis pathway could be a therapeutic approach for this disease. |
