Heterozygous knockdown insulin‐like growth factor‐1 receptor (IGF‐1R) regulates mitochondrial functions and prevents colitis and colorectal cancer

Abstract

Although insulin‐like growth factor‐1 receptor (IGF‐1R) has been accepted as a major determinant of tumorigenesis, the mechanisms of its roles in the pathogenesis of cancers have remained elusive. Herein, we demonstrate that IGF‐1R plays pivotal roles in regulation of mitochondrial functions and resistance to oxidative stress in colitis and colorectal tumorigenesis. Heterozygous knockdown IGF‐1R attenuated azoxymethane (AOM)/dextran sulfate sodium (DSS)‐induced colitis and colitis associated cancer (CAC) in Igf1r+/− mice. Knockdown of IGF‐1R confers the resistance to oxidative stress‐induced damage on colorectal epithelium through protection the mitochondrial dynamics and structures. Knockdown of IGF‐1R develops the function of mitochondrial fusion under oxidative stress. Mechanically, an increase of mitochondrial coupling index RCI and oxidative phosphorylation index ADP/O was seen in the epithelial cells of Igf1r+/− mice. Seahorse XFe‐24 analyzer analysis of mitochondrial bioenergetics showed an increase of oxygen consumption rate (OCR) and a decrease of extracellular acidification rate (ECAR) in Igf1r+/− cells. Further analysis suggests the protection mechanisms of colorectal epithelial cells from oxidative stress through activating mitochondrial respiratory chain and the LKB1/AMPK pathways. These results support the roles of IGF‐1R at the nexus between oxidative damage and mitochondrial function and connect colitis and colorectal tumorigenesis.Support or Funding InformationThis work was supported by Natural Science Foundation of China (81673449, 91629303).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.