ABSTRACT Excessive fructose intake has been associated with the development and progression of pancreatic cancer. This study aimed to elucidate the relationship between fructose utilization

and pancreatic cancer progression. Our findings revealed that pancreatic cancer cells have a high capacity to utilize fructose and are capable of converting glucose to fructose via the

_AKR1B1_-mediated polyol pathway, in addition to uptake via the fructose transporter GLUT5. Fructose metabolism exacerbates pancreatic cancer proliferation by enhancing glycolysis and

accelerating the production of key metabolites that regulate angiogenesis. However, pharmacological blockade of fructose metabolism has been shown to slow pancreatic cancer progression and

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our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS _AKR1B1_-DEPENDENT FRUCTOSE METABOLISM ENHANCES MALIGNANCY OF CANCER CELLS Article Open access 15 October 2024 THE

EFFECTS OF FRUCTOSE AND METABOLIC INHIBITION ON HEPATOCELLULAR CARCINOMA Article Open access 07 October 2020 DIETARY FRUCTOSE ENHANCES TUMOUR GROWTH INDIRECTLY VIA INTERORGAN LIPID TRANSFER

Article 04 December 2024 DATA AVAILABILITY The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

REFERENCES * Qin C, Yang G, Yang J, Ren B, Wang H, Chen G, et al. Metabolism of pancreatic cancer: paving the way to better anticancer strategies. Mol Cancer. 2020;19:50. Article  PubMed 

PubMed Central  Google Scholar  * Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet. 2011;378:607–20. Article  PubMed  PubMed Central  Google Scholar  * Siegel

RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74:12–49. Article  PubMed  Google Scholar  * Halbrook CJ, Lyssiotis CA, Pasca di Magliano M, Maitra A. Pancreatic

cancer: Advances and challenges. Cell. 2023;186:1729–54. Article  CAS  PubMed  PubMed Central  Google Scholar  * Huang L, Jansen L, Balavarca Y, Molina-Montes E, Babaei M, van der Geest L,

et al. Resection of pancreatic cancer in Europe and USA: an international large-scale study highlighting large variations. Gut. 2019;68:130–9. Article  PubMed  Google Scholar  * Strobel O,

Neoptolemos J, Jäger D, Büchler MW. Optimizing the outcomes of pancreatic cancer surgery. Nat Rev Clin Oncol. 2019;16:11–26. Article  CAS  PubMed  Google Scholar  * Herman MA, Birnbaum MJ.

Molecular aspects of fructose metabolism and metabolic disease. Cell Metab. 2021;33:2329–54. Article  CAS  PubMed  PubMed Central  Google Scholar  * Jensen T, Abdelmalek MF, Sullivan S,

Nadeau KJ, Green M, Roncal C, et al. Fructose and sugar: A major mediator of non-alcoholic fatty liver disease. J Hepatol. 2018;68:1063–75. Article  CAS  PubMed  PubMed Central  Google

Scholar  * Mirtschink P, Jang C, Arany Z, Krek W. Fructose metabolism, cardiometabolic risk, and the epidemic of coronary artery disease. Eur Heart J. 2018;39:2497–505. Article  CAS  PubMed

  Google Scholar  * Wu Y, Wong CW, Chiles EN, Mellinger AL, Bae H, Jung S, et al. Glycerate from intestinal fructose metabolism induces islet cell damage and glucose intolerance. Cell Metab.

2022;34:1042–53.e6. Article  CAS  PubMed  PubMed Central  Google Scholar  * Carreño DV, Corro NB, Cerda-Infante JF, Echeverría CE, Asencio-Barría CA, Torres-Estay VA, et al. Dietary

Fructose Promotes Prostate Cancer Growth. Cancer Res. 2021;81:2824–32. Article  PubMed  Google Scholar  * Kuehm LM, Khojandi N, Piening A, Klevorn LE, Geraud SC, McLaughlin NR, et al.

Fructose Promotes Cytoprotection in Melanoma Tumors and Resistance to Immunotherapy. Cancer Immunol Res. 2021;9:227–38. Article  CAS  PubMed  Google Scholar  * Kim J, Kang J, Kang YL, Woo J,

Kim Y, Huh J, et al. Ketohexokinase-A acts as a nuclear protein kinase that mediates fructose-induced metastasis in breast cancer. Nat Commun. 2020;11:5436. Article  CAS  PubMed  PubMed

Central  Google Scholar  * Bu P, Chen KY, Xiang K, Johnson C, Crown SB, Rakhilin N, et al. Aldolase B-Mediated Fructose Metabolism Drives Metabolic Reprogramming of Colon Cancer Liver

Metastasis. Cell Metab. 2018;27:1249–62.e4. Article  CAS  PubMed  PubMed Central  Google Scholar  * Chen WL, Wang YY, Zhao A, Xia L, Xie G, Su M, et al. Enhanced Fructose Utilization

Mediated by SLC2A5 Is a Unique Metabolic Feature of Acute Myeloid Leukemia with Therapeutic Potential. Cancer Cell. 2016;30:779–91. Article  PubMed  PubMed Central  Google Scholar  * Chen

WL, Jin X, Wang M, Liu D, Luo Q, Tian H, et al. GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC1 signaling. JCI Insight.

2020;5:e131596. Article  PubMed  PubMed Central  Google Scholar  * Shen Z, Li Z, Liu Y, Li Y, Feng X, Zhan Y, et al. GLUT5-KHK axis-mediated fructose metabolism drives proliferation and

chemotherapy resistance of colorectal cancer. Cancer Lett. 2022;534:215617. Article  CAS  PubMed  Google Scholar  * Goncalves MD, Lu C, Tutnauer J, Hartman TE, Hwang SK, Murphy CJ, et al.

High-fructose corn syrup enhances intestinal tumor growth in mice. Science. 2019;363:1345–9. Article  CAS  PubMed  PubMed Central  Google Scholar  * Jeong S, Savino AM, Chirayil R, Barin E,

Cheng Y, Park SM, et al. High Fructose Drives the Serine Synthesis Pathway in Acute Myeloid Leukemic Cells. Cell Metab. 2021;33:145–59.e6. Article  CAS  PubMed  Google Scholar  * Hannou SA,

Haslam DE, McKeown NM, Herman MA. Fructose metabolism and metabolic disease. J Clin Invest. 2018;128:545–55. Article  PubMed  PubMed Central  Google Scholar  * Han B, Wang L, Zhang J, Wei M,

Rajani C, Wei R, et al. Fructose Metabolism Contributes to the Warburg effect. bioRxiv. 2021. https://www.biorxiv.org/content/10.1101/2020.06.04.132902v4. * Kang YL, Kim J, Kwak SB, Kim YS,

Huh J, Park JW. The polyol pathway and nuclear ketohexokinase A signaling drive hyperglycemia-induced metastasis of gastric cancer. Exp Mol Med. 2024;56:220–34. Article  CAS  PubMed  PubMed

Central  Google Scholar  * Schwab A, Siddiqui A, Vazakidou ME, Napoli F, Böttcher M, Menchicchi B, et al. Polyol Pathway Links Glucose Metabolism to the Aggressiveness of Cancer Cells.

Cancer Res. 2018;78:1604–18. Article  CAS  PubMed  Google Scholar  * An YF, Pu N, Jia JB, Wang WQ, Liu L. Therapeutic advances targeting tumor angiogenesis in pancreatic cancer: Current

dilemmas and future directions. Biochim Biophys Acta Rev Cancer. 2023;1878:188958. Article  CAS  PubMed  Google Scholar  * Kerr J, Anderson C, Lippman SM. Physical activity, sedentary

behaviour, diet, and cancer: an update and emerging new evidence. Lancet Oncol. 2017;18:e457–e71. Article  PubMed  PubMed Central  Google Scholar  * Malik VS, Hu FB. The role of

sugar-sweetened beverages in the global epidemics of obesity and chronic diseases. Nat Rev Endocrinol. 2022;18:205–18. Article  PubMed  PubMed Central  Google Scholar  * Chen CH, Tsai MK,

Lee JH, Lin RT, Hsu CY, Wen C, et al. Sugar-Sweetened Beverages” Is an Independent Risk From Pancreatic Cancer: Based on Half a Million Asian Cohort Followed for 25 Years. Front Oncol.

2022;12:835901. Article  PubMed  PubMed Central  Google Scholar  * Aune D, Chan DSM, Vieira AR, Navarro Rosenblatt DA, Vieira R, Greenwood DC, et al. Dietary fructose, carbohydrates,

glycemic indices and pancreatic cancer risk: a systematic review and meta-analysis of cohort studies. Ann Oncol. 2012;23:2536–46. Article  CAS  PubMed  Google Scholar  * Huang Y, Chen Z,

Chen B, Li J, Yuan X, Li J, et al. Dietary sugar consumption and health: umbrella review. Bmj. 2023;381:e071609. Article  PubMed  PubMed Central  Google Scholar  * Krause N, Wegner A.

Fructose Metabolism in Cancer. Cells. 2020;9:2635. Article  CAS  PubMed  PubMed Central  Google Scholar  * Yabe-Nishimura C. Aldose reductase in glucose toxicity: a potential target for the

prevention of diabetic complications. Pharmacol Rev. 1998;50:21–33. CAS  PubMed  Google Scholar  * Zhang KR, Zhang YF, Lei HM, Tang YB, Ma CS, Lv QM, et al. Targeting AKR1B1 inhibits

glutathione de novo synthesis to overcome acquired resistance to EGFR-targeted therapy in lung cancer. Sci Transl Med. 2021;13:eabg6428. Article  CAS  PubMed  Google Scholar  * Wu X, Li X,

Fu Q, Cao Q, Chen X, Wang M, et al. AKR1B1 promotes basal-like breast cancer progression by a positive feedback loop that activates the EMT program. J Exp Med. 2017;214:1065–79. Article  CAS

  PubMed  PubMed Central  Google Scholar  * Kindler HL, Ioka T, Richel DJ, Bennouna J, Létourneau R, Okusaka T, et al. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients

with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 2011;12:256–62. Article  CAS  PubMed  Google Scholar  * Kindler HL, Niedzwiecki D, Hollis D,

Sutherland S, Schrag D, Hurwitz H, et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and

Leukemia Group B (CALGB 80303). J Clin Oncol. 2010;28:3617–22. Article  CAS  PubMed  PubMed Central  Google Scholar  * Hanson RL, Ho RS, Wiseberg JJ, Simpson R, Younathan ES, Blair JB.

Inhibition of gluconeogenesis and glycogenolysis by 2,5-anhydro-D-mannitol. J Biol Chem. 1984;259:218–23. Article  CAS  PubMed  Google Scholar  * Tordoff MG, Rafka R, DiNovi MJ, Friedman MI.

2,5-anhydro-D-mannitol: a fructose analogue that increases food intake in rats. Am J Physiol. 1988;254:R150–3. CAS  PubMed  Google Scholar  * Caligiuri G. CD31 as a Therapeutic Target in

Atherosclerosis. Circ Res. 2020;126:1178–89. Article  CAS  PubMed  Google Scholar  * Park S, Sorenson CM, Sheibani N. PECAM-1 isoforms, eNOS and endoglin axis in regulation of angiogenesis.

Clin Sci (Lond). 2015;129:217–34. Article  CAS  PubMed  Google Scholar  * Zhang YY, Kong LQ, Zhu XD, Cai H, Wang CH, Shi WK, et al. CD31 regulates metastasis by inducing

epithelial-mesenchymal transition in hepatocellular carcinoma via the ITGB1-FAK-Akt signaling pathway. Cancer Lett. 2018;429:29–40. Article  CAS  PubMed  Google Scholar  * Dunleavey JM, Xiao

L, Thompson J, Kim MM, Shields JM, Shelton SE, et al. Vascular channels formed by subpopulations of PECAM1+ melanoma cells. Nat Commun. 2014;5:5200. Article  CAS  PubMed  Google Scholar  *

Cui Y, Liu H, Wang Z, Zhang H, Tian J, Wang Z, et al. Fructose promotes angiogenesis by improving vascular endothelial cell function and upregulating VEGF expression in cancer cells. J Exp

Clin Cancer Res. 2023;42:184. Article  CAS  PubMed  PubMed Central  Google Scholar  * Fang JH, Chen JY, Zheng JL, Zeng HX, Chen JG, Wu CH, et al. Fructose Metabolism in Tumor Endothelial

Cells Promotes Angiogenesis by Activating AMPK Signaling and Mitochondrial Respiration. Cancer Res. 2023;83:1249–63. Article  CAS  PubMed  Google Scholar  * Zhou J, Liu T, Guo H, Cui H, Li

P, Feng D, et al. Lactate potentiates angiogenesis and neurogenesis in experimental intracerebral hemorrhage. Exp Mol Med. 2018;50:1–12. Article  PubMed  PubMed Central  Google Scholar  *

Brown TP, Ganapathy V. Lactate/GPR81 signaling and proton motive force in cancer: Role in angiogenesis, immune escape, nutrition, and Warburg phenomenon. Pharmacol Ther. 2020;206:107451.

Article  CAS  PubMed  Google Scholar  * Eelen G, Dubois C, Cantelmo AR, Goveia J, Brüning U, DeRan M, et al. Role of glutamine synthetase in angiogenesis beyond glutamine synthesis. Nature.

2018;561:63–9. Article  CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS This work was supported by Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening

(2023B1212120005). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Chinese Medicine Phenome Research Centre, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China

Chengqiang Wang, Jiao Ma, Yitao Li, Xintong Yang, Aiping Lu, Kenneth C. P. Cheung & Wei Jia * Department of Pharmacology and Pharmacy, University of Hong Kong, Hong Kong, China Lu Wang 

& Wei Jia * Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of

Medicine, Shanghai, 200233, China Qing Zhao & Junliang Kuang * NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug

Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China Huichang Bi *

Department of Experimental Medicine, University of Rome “Tor Vergata”, 00133, Rome, Italy Gerry Melino Authors * Chengqiang Wang View author publications You can also search for this author

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publications You can also search for this author inPubMed Google Scholar * Wei Jia View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS W.J.

conceptualized the study. W.J and C.W. designed the study and coordinated the experimental planning. C.W. and L.W. performed the experiments. C.W., J.M., X.Y, and Y.L. were responsible for

mouse experiments. C.W. was responsible for cell studies. C.W. and L.W. were responsible for sample preparation and metabolomics analysis. C.W. K.C. and L.W. performed the data preprocessing

and statistical analysis. C.W. and W.J. drafted the manuscript and produced the figures. G.M., A.L., H.B., Q.Z., J.K. and K.C. provided valuable suggestions in data analysis and

interpretation. W.J. and C.W. critically revised the manuscript. CORRESPONDING AUTHORS Correspondence to Kenneth C. P. Cheung, Gerry Melino or Wei Jia. ETHICS DECLARATIONS COMPETING

INTERESTS The authors declare no competing interests. ETHICS APPROVAL AND CONSENT TO PARTICIPATE All animal experiments were approved by the Research Ethics Committee of the Hong Kong

Baptist University (REC/20–21/0584) and were performed in accordance with relevant guidelines and regulations. The relevant licenses were also approved by the Department of Health, Hong

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Zhao, Q. _et al._ Exploring fructose metabolism as a potential therapeutic approach for pancreatic cancer. _Cell Death Differ_ 31, 1625–1635 (2024).

https://doi.org/10.1038/s41418-024-01394-3 Download citation * Received: 08 June 2024 * Revised: 20 September 2024 * Accepted: 27 September 2024 * Published: 15 October 2024 * Issue Date:

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