Abstract
Tumor cells have unique metabolic programming that is biologically distinct from that of corresponding normal cells. Resetting tumor metabolic programming is a promising strategy to ameliorate drug resistance and improve the tumor microenvironment. Here, we show that carboxyamidotriazole (CAI), an anticancer drug, can function as a metabolic modulator that decreases glucose and lipid metabolism and increases the dependency of colon cancer cells on glutamine metabolism. CAI suppressed glucose and lipid metabolism utilization, causing inhibition of mitochondrial respiratory chain complex I, thus producing reactive oxygen species (ROS). In parallel, activation of the aryl hydrocarbon receptor (AhR) increased glutamine uptake via the transporter SLC1A5, which could activate the ROS-scavenging enzyme glutathione peroxidase. As a result, combined use of inhibitors of GLS/GDH1, CAI could effectively restrict colorectal cancer (CRC) energy metabolism. These data illuminate a new antitumor mechanism of CAI, suggesting a new strategy for CRC metabolic reprogramming treatment.
Keywords:
2-NBDG, glucalogue 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose; ATP, adenosine triphosphate; AhR; AhR, aryl hydrocarbon receptor; CAI; CAI, carboxyamidotriazole; CHIP, chromatin immunoprecipitation; CRC, colorectal cancer; Colorectal cancer metabolism; DMF, 3′,4′-dimethoxyflavone; DNA, deoxyribonucleic acid; ECAR, extracellular acidification rate; FACS, flow cytometry; GDH1, glutamate dehydrogenase 1; GLS, glutaminase; GPx, glutathione peroxidase; GSH, glutathione; GSSG, oxidized glutathione; Glutamine metabolism; Glutaminolysis; Kyn, kynurenine; MT, mito-TEMPO; Metabolic reprogramming; Mito-Q, mitoquinone mesylate; Mitochondrial oxidative stress; OCR, oxygen consumption rate; Redox homeostasis; TCA, tricarboxylic acid; α-KG, α-ketoglutarate.