Polyol pathway-generated fructose is indispensable for growth and survival of non-small cell lung cancer.

Autor: Schwab A; Interdisciplinary Center for Clinical Research (IZKF), Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.; Experimental Medicine 1, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany., Siddiqui MA; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Ramesh V; Interdisciplinary Center for Clinical Research (IZKF), Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Gollavilli PN; Interdisciplinary Center for Clinical Research (IZKF), Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Turtos AM; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Møller SS; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Pinna L; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Havelund JF; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Rømer AMA; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Ersan PG; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.; Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey., Parma B; Interdisciplinary Center for Clinical Research (IZKF), Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.; Laboratory of Immunobiology, Université Libre de Bruxelles- Faculty of Science, Brussels, Belgium., Marschall S; Interdisciplinary Center for Clinical Research (IZKF), Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany., Dettmer K; Institute of Functional Genomics, University of Regensburg, Regensburg, Germany., Alhusayan M; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Bioenergetics & Neurometabolism, Dasman Diabetes Institute, Dasman, Kuwait., Bertoglio P; Division of Thoracic Surgery, IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy., Querzoli G; Pathology Unit, IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy.; Ospedale Sacro Cuore Don Calabria, Verona, Italy., Mielenz D; Division of Molecular Immunology, Department of Internal Medicine 3, Friedrich-Alexander Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Nikolaus-Fiebiger-Center, Erlangen, Germany., Sahin O; Department of Biochemistry & Molecular Biology - College of Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA., Færgeman NJ; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Asangani IA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Ceppi P; Interdisciplinary Center for Clinical Research (IZKF), Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany. pceppi@bmb.sdu.dk.; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark. pceppi@bmb.sdu.dk.
Jazyk: angličtina
Zdroj: Cell death and differentiation [Cell Death Differ] 2024 Nov 20. Date of Electronic Publication: 2024 Nov 20.
DOI: 10.1038/s41418-024-01415-1
Abstrakt: Despite recent treatment advances, non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related deaths worldwide, and therefore it necessitates the exploration of new therapy options. One commonly shared feature of malignant cells is their ability to hijack metabolic pathways to confer survival or proliferation. In this study, we highlight the importance of the polyol pathway (PP) in NSCLC metabolism. This pathway is solely responsible for metabolizing glucose to fructose based on the enzymatic activity of aldose reductase (AKR1B1) and sorbitol dehydrogenase (SORD). Via genetic and pharmacological manipulations, we reveal that PP activity is indispensable for NSCLC growth and survival in vitro and in murine xenograft models. Mechanistically, PP deficiency provokes multifactorial deficits, ranging from energetic breakdown and DNA damage, that ultimately trigger the induction of apoptosis. At the molecular level, this process is driven by pro-apoptotic JNK signaling and concomitant upregulation of the transcription factors c-Jun and ATF3. Moreover, we show that fructose, the PP end-product, as well as other non-glycolytic hexoses confer survival to cancer cells and resistance against chemotherapy via sustained NF-κB activity as well as an oxidative switch in metabolism. Given the detrimental consequence of PP gene targeting on growth and survival, we propose PP pathway interference as a viable therapeutic approach against NSCLC.
Competing Interests: Competing interests: OS is the co-founder and manager of OncoCube Therapeutics LLC, founder, and president of LoxiGen, and the member of scientific advisory board of A2A Pharmaceuticals Inc. The other authors declare no conflict of interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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