AKR1B8 IS A NOVEL MODULATOR OF CRYPTIC SELF-RENEWAL AND SUSCEPTIBILITY TO COLITIS AND ASSOCIATED CANCER
type: CreativeWork
description: Aldo-keto reductase 1B10 (AKR1B10) promotes cell growth and proliferation via eliminating cytotoxic carbonyls and mediating fatty acid/lipid synthesis, and induces drug resistance to cytostatic antitumor agents containing carbonyl groups such as daunorubicin, resulting in failure of treatment. AKR1B10 may also participate in cell differentiation and carcinogenesis by depleting the precursor of cellular retinoic acid, a signaling molecule, and activating pro-carcinogens, such as polycyclic aromatic hydrocarbon (PAH). AKR1B10 is primarily expressed in human colonic mucosa, but its biochemistry, biological functions, and pathological roles in normal and diseased conditions of the colon remain unclear. In this study, we characterized the biochemical properties of AKR1B10 protein and investigated its pathophysiological roles in colonic diseases. The reversible thiol/disulfide exchange is an important regulatory mechanism of protein enzymatic activity. Many protein enzymes are susceptible to S-thiolation induced by reactive oxygen species (ROS); and physiological thiols, glutathione (GSH) and free amino acid cysteine (Cys), are critical intracellular thiol antioxidants, protecting proteins from irreversible oxidative damage. AKR1B10 contains 4 Cys residues, i.e., Cys45, Cys187, Cys200, and Cys299; and in the 3D structure, the Cys299, a key residue for AKR1B10 enzymatic activity, is located to the Cys187 at 10.45 Å. Exposing AKR1B10 to ROS resulted in significant decrease of its free sulfhydryl groups, up to 40% and 50% when 0.5 or 1.0 mM Cys was used in the ROS mixture, respectively; accordingly, AKR1B10 activity was decreased in parallel with the oxidation of the sulfhydryl groups, ranked as ROS with Cys >> ROS with GSH > ROS. ROS-induced thiolation also affected the sensitivity of AKR1B10 to inhibitors EBPC, epalrestat, and statil. Ulcerative colitis (UC) and colitis-associated colorectal cancer (CAC) is a serious health problem, but etiopathological factors remain uncl…
abstract: Aldo-keto reductase 1B10 (AKR1B10) promotes cell growth and proliferation via eliminating cytotoxic carbonyls and mediating fatty acid/lipid synthesis, and induces drug resistance to cytostatic antitumor agents containing carbonyl groups such as daunorubicin, resulting in failure of treatment. AKR1B10 may also participate in cell differentiation and carcinogenesis by depleting the precursor of cellular retinoic acid, a signaling molecule, and activating pro-carcinogens, such as polycyclic aromatic hydrocarbon (PAH). AKR1B10 is primarily expressed in human colonic mucosa, but its biochemistry, biological functions, and pathological roles in normal and diseased conditions of the colon remain unclear. In this study, we characterized the biochemical properties of AKR1B10 protein and investigated its pathophysiological roles in colonic diseases. The reversible thiol/disulfide exchange is an important regulatory mechanism of protein enzymatic activity. Many protein enzymes are susceptible to S-thiolation induced by reactive oxygen species (ROS); and physiological thiols, glutathione (GSH) and free amino acid cysteine (Cys), are critical intracellular thiol antioxidants, protecting proteins from irreversible oxidative damage. AKR1B10 contains 4 Cys residues, i.e., Cys45, Cys187, Cys200, and Cys299; and in the 3D structure, the Cys299, a key residue for AKR1B10 enzymatic activity, is located to the Cys187 at 10.45 Å. Exposing AKR1B10 to ROS resulted in significant decrease of its free sulfhydryl groups, up to 40% and 50% when 0.5 or 1.0 mM Cys was used in the ROS mixture, respectively; accordingly, AKR1B10 activity was decreased in parallel with the oxidation of the sulfhydryl groups, ranked as ROS with Cys >> ROS with GSH > ROS. ROS-induced thiolation also affected the sensitivity of AKR1B10 to inhibitors EBPC, epalrestat, and statil. Ulcerative colitis (UC) and colitis-associated colorectal cancer (CAC) is a serious health problem, but etiopathological factors remain uncl…
author: Shen, Yi
date published: 2014-05-01T07:00:00Z
date modified: 2026-07-24T04:34:30Z
provider: Southern Illinois University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Southern Illinois University