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

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.

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Publication Details

Journal
Cell Death and Differentiation
Published
2024-11-20
DOI
https://doi.org/10.1038/s41418-024-01415-1
Citations
18
Primary Topic
Diet, Metabolism, and Disease
Type
article
Field-Weighted Citation Impact
6.44

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article

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

Paradesi Naidu Gollavilli, Luisa Pinna, Annemarie Schwab, Pelin G. Ersan et al.
18 citations
Cell Death and Differentiation
Diet, Metabolism, and Disease
6.44
article

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

Paradesi Naidu Gollavilli, Luisa Pinna, Annemarie Schwab, Pelin G. Ersan, Pietro Bertoglio, Giulia Querzoli, Özgür Şahin, Beatrice Parma, Vignesh Ramesh, Nils Joakim Færgeman, Paolo Ceppi, Aarif Siddiqui, Dirk Mielenz, Adriana Martinez-Turtos, Sabine Marschall, Katja Dettmer, Jesper Foged Havelund, Irfan A. Asangani, Mohammed Alhusayan, Anne Mette A. Rømer, Sarah Søgaard Møller
article en
18 citations

Abstract

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.

Cell Death and DifferentiationVol. 32(4)
University of Copenhagen (DK), Université Libre de Bruxelles (BE), Medical University of South Carolina (US), Bilkent University (TR), University of Southern Denmark (DK), Friedrich-Alexander-Universität Erlangen-Nürnberg (DE), Universitätsklinikum Erlangen (DE), MUSC Hollings Cancer Center (US), Ospedale Sacro Cuore Don Calabria (IT), Azienda USL di Bologna (IT), Dasman Diabetes Institute (KW), University of Regensburg (DE), University of Pennsylvania (US)
U.S. Department of Defense, Kræftens Bekæmpelse, Kuwait Foundation for the Advancement of Sciences, Lundbeckfonden, Novo Nordisk, Danmarks Frie Forskningsfond, Deutsche Krebshilfe, Syddansk Universitet, Novo Nordisk Fonden, H. Lundbeck A/S, National Cancer Institute
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Openalex Percentile: Top 3%
Diet, Metabolism, and Disease
6.44
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