title: Targeting the metabolic pathway of human colon cancer overcomes resistance to TRAIL-induced apoptosis.
abstract: Colon cancer is a leading cause of cancer-related mortality for which targeted therapy is needed; however, trials using apoptosis-inducing ligand monotherapy to overcome resistance to apoptosis have not shown clinical responses. Since colon cancer cells selectively uptake and rapidly metabolize glucose, a property utilized for clinical staging, we investigated mechanisms to alter glucose metabolism in order to selectively target the cancer cells and to overcome evasion of apoptosis. We demonstrate TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) resistance in the majority of human colon cancers tested and utilize the glucose analog 2-deoxy-d-glucose to sensitize TRAIL-resistant gastrointestinal adenocarcinoma cells, and not normal gastrointestinal epithelial cells, to TRAIL-induced apoptosis through enhanced death receptor 5 expression, downstream modulation of MAPK signaling and subsequent miRNA expression modulation by increasing the expression of miR-494 via MEK activation. Further, established human colon cancer xenografts treated with this strategy experience anti-tumor responses. These findings in colon adenocarcinoma support further investigation of manipulation of cellular energetics to selectively overcome resistance to apoptosis and to impart tumor regressions in established colon cancer tumors.
authors.affiliation: Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA; Department of Microbiology & Immunology, University of Illinois at Chicago, College of Medicine, 835S. Wolcott Ave., MC790, Chicago, IL 60612, USA.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Carr
authors.affiliation: Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, College of Medicine , Chicago, IL 60612, USA.
authors.forename: Guilin
authors.initials: G
authors.lastname: Qiao
authors.affiliation: Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, College of Medicine , Chicago, IL 60612, USA.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Qin
authors.affiliation: Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, College of Medicine , Chicago, IL 60612, USA.
authors.forename: Sundararajan
authors.initials: S
authors.lastname: Jayaraman
authors.affiliation: Department of Microbiology & Immunology, University of Illinois at Chicago, College of Medicine , 835S. Wolcott Ave., MC790, Chicago, IL 60612, USA.
authors.forename: Bellur S
authors.initials: BS
authors.lastname: Prabhakar
authors.affiliation: Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA; Department of Microbiology & Immunology, University of Illinois at Chicago, College of Medicine, 835S. Wolcott Ave., MC790, Chicago, IL 60612, USA; The Creticos Cancer Center at Advocate Illinois Masonic Medical Center, Chicago, IL 60657, USA.
authors.forename: Ajay V
authors.initials: AV
authors.lastname: Maker