Schwab, Annemarie and Siddiqui, Mohammad Aarif and Ramesh, Vignesh and Gollavilli, Paradesi Naidu and Turtos, Adriana Martinez and Moller, Sarah Sogaard and Pinna, Luisa and Havelund, Jesper F. and Romer, Anne Mette A. and Ersan, Pelin Guelizar and Parma, Beatrice and Marschall, Sabine and Dettmer, Katja and Alhusayan, Mohammed and Bertoglio, Pietro and Querzoli, Giulia and Mielenz, Dirk and Sahin, Ozgur and Faergeman, Nils J. and Asangani, Irfan A. and Ceppi, Paolo (2025) Polyol pathway-generated fructose is indispensable for growth and survival of non-small cell lung cancer. CELL DEATH AND DIFFERENTIATION, 32 (4). pp. 587-597. ISSN 1350-9047, 1476-5403
Full text not available from this repository. (Request a copy)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-kappa B 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ACTIVATING TRANSCRIPTION FACTOR-3; SIGNALING PATHWAY; INDUCED APOPTOSIS; ALDOSE; HEPATOCYTES; REDUCTASES; EXPRESSION; INDUCTION; AKR1B1; EMT; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 31 Mar 2026 09:04 |
| Last Modified: | 31 Mar 2026 09:04 |
| URI: | https://pred.uni-regensburg.de/id/eprint/65435 |
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