A hexokinase isoenzyme switch in human liver cancer cells promotes lipogenesis and enhances innate immunity
Year: 2021
Type: article
Abstract: During the cancerous transformation of normal hepatocytes into hepatocellular carcinoma (HCC), the enzyme catalyzing the first rate-limiting step of glycolysis, namely the glucokinase (GCK), is replaced by the higher affinity isoenzyme, hexokinase 2 (HK2). Here, we show that in HCC tumors the highest expression level of HK2 is inversely correlated to GCK expression, and is associated to poor prognosis for patient survival. To further explore functional consequences of the GCK-to-HK2 isoenzyme switch occurring during carcinogenesis, HK2 was knocked-out in the HCC cell line Huh7 and replaced by GCK, to generate the Huh7-GCK+/HK2− cell line. HK2 knockdown and GCK expression rewired central carbon metabolism, stimulated mitochondrial respiration and restored essential metabolic functions of normal hepatocytes such as lipogenesis, VLDL secretion, glycogen storage. It also reactivated innate immune responses and sensitivity to natural killer cells, showing that consequences of the HK switch extend beyond metabolic reprogramming.
Source: Communications Biology
Institutions: Lyon 1 Université, Centre National de la Recherche Scientifique, Inserm, Centre International de Recherche en Infectiologie, Helmholtz Munich, Hôpital Lyon Sud, Laboratoire de recherche en cardiovasculaire, métabolisme, diabétologie et nutrition, Institut National des Sciences Appliquées de Lyon, École Normale Supérieure de Lyon, Université de Lyon, Centre de RMN à Très Hauts Champs de Lyon, Constructor University, Maladies Rares: Génétique et Métabolisme, Technical University of Munich
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,890
Funders: National Science Foundation, U.S. Department of Health and Human Services, Bundesverband der Deutschen Industrie, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale, Centre National de la Recherche Scientifique, Université Claude Bernard Lyon 1, École Normale Supérieure de Lyon, National Cancer Institute, National Institute of General Medical Sciences
Awards: G1326425543, Tumor pyruvate kinase as key regulator of cancer metabolism, G3339627588, G3813211901, G4473744192, Tumor pyruvate kinase as key regulator of cancer metabolism, G5478279944, G6741304127, Fresno State and UC Merced Bridges to the Doctorate Program in Biomedical and Behavioral Sciences
OpenAlex ID: W3132358611