{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T04:30:17Z","timestamp":1786336217995,"version":"build-2736575974"},"reference-count":49,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T00:00:00Z","timestamp":1786147200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010607","name":"University of Perugia","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100010607","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/00x27da85","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Individuals with Laron syndrome, a rare condition characterized by congenital insulin-like growth factor 1 (IGF-1) deficiency, display a remarkably low incidence of cancer, suggesting the existence of protective mechanisms linking reduced IGF-1 signaling to decreased cancer susceptibility. Consistent with this observation, IGF-1 is a recognized promoter of prostate cancer (PCa) progression, although the underlying mechanisms remain incompletely understood. Methylglyoxal (MG)-derived glycative stress, reflected by the accumulation of MG-derived hydroimidazolone 1 (MG-H1), has been implicated in PCa progression but has never been investigated in Laron syndrome. We found that liver tissues from Laron mice exhibited lower MG-H1 levels, suggesting reduced MG-derived glycative stress associated with low IGF-1 signaling. These findings prompted us to investigate whether MG-derived glycative stress contributes to IGF-1-driven PCa progression. Compared with the less aggressive LNCaP cells, PC3 cells displayed higher basal IGF-1 and MG-H1 levels, consistent with a potential association between IGF-1 and MG-derived glycative stress in PCa progression. Moreover, IGF-1 stimulation of LNCaP cells increased MG-H1 accumulation, proliferation, colony formation, invasiveness, and gene expression of matrix metalloproteinase (MMP)-1, MMP-7, MMP-9, receptor for advanced glycation end-products (RAGE), and Osteopontin (OPN), all of which were markedly attenuated by the MG scavenger aminoguanidine (AG). Collectively, these findings support a potential contribution of MG-derived glycative stress to IGF-1-driven PCa progression.<\/jats:p>","DOI":"10.3390\/biology15161342","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T01:20:03Z","timestamp":1786324803000},"page":"1342","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Laron Syndrome Mouse Model Reveals a Potential Contribution of Methylglyoxal-Derived Glycative Stress to IGF-1-Driven Prostate Cancer Progression"],"prefix":"10.3390","volume":"15","author":[{"given":"Dominga","family":"Manfredelli","sequence":"first","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Torcoli","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cinzia","family":"Lilli","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catia","family":"Bellucci","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo N.","family":"Talesa","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6562-5923","authenticated-orcid":false,"given":"Francesca","family":"Mancuso","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziano","family":"Baroni","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8259-680X","authenticated-orcid":false,"given":"Cinzia","family":"Antognelli","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,8]]},"reference":[{"key":"ref_1","first-page":"101293","article-title":"Theranostic strategies in prostate cancer: Advances in PSMA PET imaging and radioligand therapy","volume":"48","author":"Han","year":"2026","journal-title":"Cancer Treat. Res. Commun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e71259","DOI":"10.1111\/jcmm.71259","article-title":"METTL3\/YTHDF1-Driven SURF6 Promotes Prostate Cancer Stemness via CDK4","volume":"30","author":"Cheng","year":"2026","journal-title":"J. Cell Mol. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3381","DOI":"10.1097\/CM9.0000000000003844","article-title":"Revisiting the role of metabolic reprogramming as a contributor to prostate cancer disease progression","volume":"138","author":"Ding","year":"2025","journal-title":"Chin. Med. J. (Engl.)"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"103444","DOI":"10.1016\/j.neuro.2026.103444","article-title":"Capsaicin attenuates methylglyoxal-induced neurotoxicity via the ATF4-Sestrin2 signaling and direct scavenging of methylglyoxal","volume":"114","author":"Koike","year":"2026","journal-title":"Neurotoxicology"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Aragon\u00e8s, G., Rowan, S., Francisco, S.G., Whitcomb, E.A., Yang, W., Perini-Villanueva, G., Schalkwijk, C.G., Taylor, A., and Bejarano, E. (2021). The Glyoxalase System in Age-Related Diseases: Nutritional Intervention as Anti-Ageing Strategy. Cells, 10.","DOI":"10.3390\/cells10081852"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1152\/physrev.00001.2019","article-title":"Methylglyoxal, a Highly Reactive Dicarbonyl Compound, in Diabetes, Its Vascular Complications, and Other Age-Related Diseases","volume":"100","author":"Schalkwijk","year":"2020","journal-title":"Physiol. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1042\/CS20140683","article-title":"The role of methylglyoxal and the glyoxalase system in diabetes and other age-related diseases","volume":"128","author":"Maessen","year":"2015","journal-title":"Clin. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Wang, Z., Liu, S., Zhang, M., and Liu, M. (2025). Dual roles of methylglyoxal in cancer. Front. Oncol., 15.","DOI":"10.3389\/fonc.2025.1557162"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2865","DOI":"10.1111\/jcmm.13581","article-title":"Glyoxalase 1 sustains the metastatic phenotype of prostate cancer cells via EMT control","volume":"22","author":"Antognelli","year":"2018","journal-title":"J. Cell Mol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Antognelli, C., Mandarano, M., Prosperi, E., Sidoni, A., and Talesa, V.N. (2021). Glyoxalase-1-Dependent Methylglyoxal Depletion Sustains PD-L1 Expression in Metastatic Prostate Cancer Cells: A Novel Mechanism in Cancer Immunosurveillance Escape and a Potential Novel Target to Overcome PD-L1 Blockade Resistance. Cancers, 13.","DOI":"10.3390\/cancers13122965"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Antognelli, C., Marinucci, L., Frosini, R., Macchioni, L., and Talesa, V.N. (2021). Metastatic Prostate Cancer Cells Secrete Methylglyoxal-Derived MG-H1 to Reprogram Human Osteoblasts into a Dedifferentiated, Malignant-like Phenotype: A Possible Novel Player in Prostate Cancer Bone Metastases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910191"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Manfredelli, D., Armeni, T., de Bari, L., Scir\u00e8, A., Talesa, V.N., Antognelli, C., and Pariano, M. (2025). Acetylcholine Sustains LNCaP Prostate Cancer Cell Migration, Invasion and Proliferation Through Glyoxalase 1\/MG-H1 Axis with the Involvement of Osteopontin. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26094107"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Manfredelli, D., Torcoli, C., Pariano, M., Bellezza, G., Baroni, T., Talesa, V.N., Sidoni, A., and Antognelli, C. (2025). PTEN\/PKM2\/ER\u03b1-Driven Glyoxalase 1 Overexpression Sustains PC3 Prostate Cancer Cell Growth Through MG-H1\/RAGE Pathway Desensitization Leading to H2O2-Dependent KRIT1 Downregulation. Antioxidants, 14.","DOI":"10.3390\/antiox14091120"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Liu, G., Zhu, M., Zhang, M., and Pan, F. (2023). Emerging Role of IGF-1 in Prostate Cancer: A Promising Biomarker and Therapeutic Target. Cancers, 15.","DOI":"10.3390\/cancers15041287"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Rajoria, B., Zhang, X., and Yee, D. (2023). IGF-1 Stimulates Glycolytic ATP Production in MCF-7L Cells. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241210209"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Kasprzak, A. (2021). Insulin-Like Growth Factor 1 (IGF-1) Signaling in Glucose Metabolism in Colorectal Cancer. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126434"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Manfrini, S., Malgeri, A., Mone, C., Francesco, L.D., Pecora, G., Mazzilli, R., Defeudis, G., Khazrai, M.Y., and Faggiano, A. (2026). Ketogenic and Low-Carbohydrate Diets in Prostate Cancer: Metabolic Rationale, Preclinical Evidence, and Preliminary Clinical Data. J. Clin. Med., 15.","DOI":"10.3390\/jcm15103946"},{"key":"ref_18","first-page":"1","article-title":"Carbohydrates and cancer: A metabolic and epidemiological overview","volume":"87","author":"Mir","year":"2025","journal-title":"Adv. Carbohydr. Chem. Biochem"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Werner, H., Sarfstein, R., Nagaraj, K., and Laron, Z. (2020). Laron Syndrome Research Paves the Way for New Insights in Oncological Investigation. Cells, 9.","DOI":"10.3390\/cells9112446"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.3724\/abbs.2026005","article-title":"Multifaceted elucidation of aminoguanidine in protecting against diabetes-induced vascular endothelial injury","volume":"58","author":"Tang","year":"2026","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"149423","DOI":"10.1016\/j.foodchem.2026.149423","article-title":"Mechanism study on the inhibition of lactoferrin glycation and AGEs production by pineapple Peel polyphenols based on molecular interaction and antioxidant synergy","volume":"517","author":"Xin","year":"2026","journal-title":"Food Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2553","DOI":"10.1016\/j.ajpath.2018.07.013","article-title":"Testosterone and Follicle Stimulating Hormone-Dependent Glyoxalase 1 Up-Regulation Sustains the Viability of Porcine Sertoli Cells through the Control of Hydroimidazolone- and Argpyrimidine-Mediated NF-\u03baB Pathway","volume":"188","author":"Antognelli","year":"2018","journal-title":"Am. J. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Siech, C., Rutz, J., Maxeiner, S., Grein, T., Sonnenburg, M., Tsaur, I., Chun, F.K., and Blaheta, R.A. (2022). Insulin-like Growth Factor-1 Influences Prostate Cancer Cell Growth and Invasion through an Integrin \u03b13, \u03b15, \u03b1V, and \u03b21 Dependent Mechanism. Cancers, 14.","DOI":"10.3390\/cancers14020363"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Ortiz-Hern\u00e1ndez, G.L., Patrick, C., Hinz, S., LaBarge, M.A., Li, Y.R., and Neuhausen, S.L. (2025). CYR61 Expression Is Induced by IGF1 and Promotes the Proliferation of Prostate Cancer Cells Through the PI3\/AKT Signaling Pathway. Int. J. Mol. Sci., 26.","DOI":"10.20944\/preprints202506.1261.v1"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"107157","DOI":"10.18632\/oncotarget.22362","article-title":"Insulin-like growth factor-I induces chemoresistence to docetaxel by inhibiting miR-143 in human prostate cancer","volume":"8","author":"Niu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s11154-020-09600-6","article-title":"Mouse models of growth hormone insensitivity","volume":"22","author":"Young","year":"2021","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"13215","DOI":"10.1073\/pnas.94.24.13215","article-title":"A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor\/binding protein gene (the Laron mouse)","volume":"94","author":"Zhou","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time PCR data by the comparative CT method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1002\/2211-5463.13627","article-title":"High growth hormone serum partially protects mice against Trypanosoma cruzi infection","volume":"13","author":"Basu","year":"2023","journal-title":"FEBS Open Bio"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"153887","DOI":"10.1016\/j.tox.2024.153887","article-title":"Methylglyoxal-derived hydroimidazolone-1\/RAGE axis induces renal oxidative stress and renal fibrosis in vitro and in vivo","volume":"507","author":"Kim","year":"2024","journal-title":"Toxicology"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Silver, S.V., and Popovics, P. (2023). The Multifaceted Role of Osteopontin in Prostate Pathologies. Biomedicines, 11.","DOI":"10.3390\/biomedicines11112895"},{"key":"ref_32","first-page":"369","article-title":"Co-expression of RAGE and HMGB1 is associated with cancer progression and poor patient outcome of prostate cancer","volume":"4","author":"Zhao","year":"2014","journal-title":"Am. J. Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1158\/0008-5472.CAN-05-2816","article-title":"Increased expression of osteopontin contributes to the progression of prostate cancer","volume":"66","author":"Khodavirdi","year":"2006","journal-title":"Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1007\/s12672-018-0342-9","article-title":"RAGE and Its Ligands: Molecular Interplay Between Glycation, Inflammation, and Hallmarks of Cancer-a Review","volume":"9","author":"Palanissami","year":"2018","journal-title":"Horm. Cancer"},{"key":"ref_35","first-page":"508","article-title":"Expression of high-mobility groups box-1\/receptor for advanced glycation end products\/osteopontin\/early growth response-1 pathway in proliferative vitreoretinal epiretinal membranes","volume":"17","author":"Missotten","year":"2011","journal-title":"Mol. Vis."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Chiavarina, B., Nokin, M.J., Bellier, J., Durieux, F., Bletard, N., Sherer, F., Lovinfosse, P., Peulen, O., Verset, L., and Dehon, R. (2017). Methylglyoxal-Mediated Stress Correlates with High Metabolic Activity and Promotes Tumor Growth in Colorectal Cancer. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18010213"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s13058-018-1095-7","article-title":"Methylglyoxal, a glycolysis metabolite, triggers metastasis through MEK\/ERK\/SMAD1 pathway activation in breast cancer","volume":"21","author":"Nokin","year":"2019","journal-title":"Breast Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e19375","DOI":"10.7554\/eLife.19375","article-title":"Methylglyoxal, a glycolysis side-product, induces Hsp90 glycation and YAP-mediated tumor growth and metastasis","volume":"5","author":"Nokin","year":"2016","journal-title":"Elife"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1038\/s41585-024-00942-3","article-title":"Interactions between androgen and IGF1 axes in prostate tumorigenesis","volume":"22","author":"Adzavon","year":"2025","journal-title":"Nat. Rev. Urol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"38422","DOI":"10.1038\/s41598-025-22288-5","article-title":"IGF-1 regulates cancer cell immune evasion in prostate cancer","volume":"15","author":"Nandakumar","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Wang, J., Yang, X., Wang, Z., and Wang, J. (2022). Role of the Glyoxalase System in Breast Cancer and Gynecological Cancer-Implications for Therapeutic Intervention: A Review. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.857746"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.3390\/cancers6031298","article-title":"Roles of matrix metalloproteinases and their natural inhibitors in prostate cancer progression","volume":"6","author":"Gong","year":"2014","journal-title":"Cancers"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3233\/CBM-170901","article-title":"Effects of various treatment approaches for treatment efficacy for late stage breast cancer and expression level of TIMP-1 and MMP-9","volume":"23","author":"Yuan","year":"2018","journal-title":"Cancer Biomark."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Lipka, U., Orywal, K., and Gudowska-Sawczuk, M. (2026). Matrix Metalloproteinases and Pro-Inflammatory Cytokines in Bladder Cancer: Diagnostic and Prognostic Perspectives: Narrative Review. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27073218"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1002\/pros.20718","article-title":"Differential localization of MT1-MMP in human prostate cancer tissue: Role of IGF-1R in MT1-MMP expression","volume":"68","author":"Sroka","year":"2008","journal-title":"Prostate"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1530\/ERC-16-0054","article-title":"Identification of signaling pathways associated with cancer protection in Laron syndrome","volume":"23","author":"Rotem","year":"2016","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.mrrev.2016.08.002","article-title":"IGF-I deficiency, longevity and cancer protection of patients with Laron syndrome","volume":"772","author":"Laron","year":"2017","journal-title":"Mutat. Res. Rev. Mutat. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e220394","DOI":"10.1530\/ERC-22-0394","article-title":"Congenital IGF-1 deficiency protects from cancer: Lessons from Laron syndrome","volume":"30","author":"Laron","year":"2023","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1016\/j.tig.2025.05.003","article-title":"The rare-to-common disease journey: A winding road to new therapies","volume":"41","author":"Reinholdt","year":"2025","journal-title":"Trends Genet."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/16\/1342\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T04:11:00Z","timestamp":1786335060000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/16\/1342"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,8]]},"references-count":49,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["biology15161342"],"URL":"https:\/\/doi.org\/10.3390\/biology15161342","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,8]]}}}