Wang 2019 Free Radic Biol Med
|Wang SQ, Yang XY, Cui SX, Gao ZH, Qu XJ (2019) Heterozygous knockout insulin-like growth factor-1 receptor (IGF-1R) regulates mitochondrial functions and prevents colitis and colorectal cancer. Free Radic Biol Med 134:87-98.|
Abstract: Although insulin-like growth factor-1 receptor (IGF-1R) has been accepted as a major determinant of cancers, its biological roles and corresponding mechanisms in tumorigenesis have remained elusive. Herein, we demonstrate that IGF-1R plays pivotal roles in the regulation of mitochondrial respiratory chain and functions during colitis and tumorigenesis. Heterozygous knockout IGF-1R attenuated azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis and colitis associated cancer (CAC) in Igf1r+/- mice. Heterozygous knockout IGF-1R confers resistance to oxidative stress-induced damage on colorectal epithelial cells by protecting mitochondrial dynamics and structures. IGF-1R low expression improves the biological function of mitochondrial fusion under oxidative stress. Mechanically, an increase in respiratory coupling index (RCI) and oxidative phosphorylation index (ADP/O) was seen in colorectal epithelial cells of Igf1r+/- mice. Seahorse XFe-24 analyzer analysis of mitochondrial bioenergetics demonstrated an increase in oxygen consumption rate (OCR) and a decrease of extracellular acidification rate (ECAR) in Igf1r+/- cells. Further analysis suggests the protection mechanisms of Igf1r+/- cells from oxidative stress through the activation of the mitochondrial respiratory chain and LKB1/AMPK pathways. These results highlight the biological roles of IGF-1R at the nexus between oxidative damage and mitochondrial function and a connection between colitis and colorectal cancer.
Copyright © 2019 Elsevier Inc. All rights reserved.
• Keywords: Colitis-associated cancer, IGF-1R, LKB1/AMPK pathways, Mitochondrial functions, Oxidative stress, Ulcerative colitis • Bioblast editor: Plangger M
Labels: MiParea: Respiration, Genetic knockout;overexpression Pathology: Cancer Stress:Oxidative stress;RONS Organism: Mouse Tissue;cell: Heart, Liver, Endothelial;epithelial;mesothelial cell Preparation: Isolated mitochondria
Coupling state: LEAK, OXPHOS