{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:24Z","timestamp":1787028564124,"version":"build-2736575974"},"reference-count":56,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T00:00:00Z","timestamp":1745884800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health (USA)","award":["R01ES030572"],"award-info":[{"award-number":["R01ES030572"]}]},{"name":"National Institute of Health (USA)","award":["R01CA217923"],"award-info":[{"award-number":["R01CA217923"]}]},{"name":"National Institute of Health (USA)","award":["R01CA229234"],"award-info":[{"award-number":["R01CA229234"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lung cancer is the leading cause of cancer deaths among American men, even though various treatments are available. The discovery and use of new alternative drugs to treat lung cancers are needed to reduce lung cancer mortality. Phytochemicals are potentially desirable therapeutic agents due to their better safety profiles. Isorhapontigenin (ISO) is an orally bioavailable dietary stilbene. Our studies show that treatment with ISO inhibits human lung cancer cell growth, angiogenesis, invasion, and migration. Neural precursor cell expressed developmentally downregulated 9 (NEDD9), a multi-domain scaffolding protein, regulates various processes crucial for tumorigenesis and metastasis. Our results show that NEDD9 is upregulated in the lung tissues from human lung adenocarcinomas (LUADs) and squamous-cell carcinomas (LUSCs) compared to normal lungs. Overexpression of NEDD9 elevates the invasion and migration of human lung cancer cells. Treatment of human lung cancer cells with ISO decreases NEDD9 protein levels. Our studies have also demonstrated that NEDD9 positively regulates angiogenesis, an essential factor in cancer progression. ISO treatment reduces angiogenesis. Moreover, ISO reduces the protein levels of hypoxia-inducible factor-1\u03b1 (HIF-1\u03b1), a transcription factor critical for angiogenesis. Aberrant high expression of \u03b2-Catenin leads to various diseases including cancer. Our results show that ISO treatment reduces the activation of \u03b2-Catenin through the downregulation of NEDD9. Studies indicate that ISO decreases NEDD9, causing the suppression of cell growth, angiogenesis, invasion, and migration of human lung cancer cells. ISO is a potent therapeutic agent for lung cancer treatment.<\/jats:p>","DOI":"10.3390\/ijms26094207","type":"journal-article","created":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T07:49:36Z","timestamp":1745912976000},"page":"4207","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Isorhapontigenin Inhibits Cell Growth, Angiogenesis, Migration, and Invasion of Non-Small-Cell Lung Cancer Cells Through NEDD9 Signaling"],"prefix":"10.3390","volume":"26","author":[{"given":"Zhuo","family":"Zhang","sequence":"first","affiliation":[{"name":"Division of Environmental Medicine, Department of Medicine, New York University Grossman School of Medicine, 341 E 25th Street, New York, NY 10010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingxia","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Environmental Medicine, Department of Medicine, New York University Grossman School of Medicine, 341 E 25th Street, New York, NY 10010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daneah","family":"Willis","sequence":"additional","affiliation":[{"name":"Division of Environmental Medicine, Department of Medicine, New York University Grossman School of Medicine, 341 E 25th Street, New York, NY 10010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Shi","sequence":"additional","affiliation":[{"name":"Division of Environmental Medicine, Department of Medicine, New York University Grossman School of Medicine, 341 E 25th Street, New York, NY 10010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0865-7886","authenticated-orcid":false,"given":"Huailu","family":"Tu","sequence":"additional","affiliation":[{"name":"Division of Environmental Medicine, Department of Medicine, New York University Grossman School of Medicine, 341 E 25th Street, New York, NY 10010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Costa","sequence":"additional","affiliation":[{"name":"Division of Environmental Medicine, Department of Medicine, New York University Grossman School of Medicine, 341 E 25th Street, New York, NY 10010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,29]]},"reference":[{"key":"ref_1","unstructured":"(2025, January 28). Available online: https:\/\/www.cancer.org\/cancer\/types\/lung-cancer\/about\/key-statistics.html."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/s41572-024-00551-9","article-title":"Non-small-cell lung cancer","volume":"10","author":"Hendriks","year":"2024","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","unstructured":"(2025, January 28). Available online: https:\/\/www.lung.org\/research\/trends-in-lung-disease\/lung-cancer-trends-brief\/lung-cancer-prevalence-and-incidence-(1)."},{"key":"ref_4","unstructured":"(2025, January 28). Available online: https:\/\/www.lung.org\/research\/trends-in-lung-disease\/lung-cancer-trends-brief."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Ko, J.H., Sethi, G., Um, J.Y., Shanmugam, M.K., Arfuso, F., Kumar, A.P., Bishayee, A., and Kwang Ahn, S. (2017). The Role of Resveratrol in Cancer Therapy. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18122589"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Dai, Y., Wang, J., Yang, Y., Jin, H., Liu, F., Liu, H., Ho, P.C., and Lin, H.S. (2024). Exploration of Nutraceutical Potentials of Isorhapontigenin, Oxyresveratrol, and Pterostilbene: A Metabolomic Approach. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252011027"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Dai, Y., Yeo, S.C., Barnes, P.I., Donnelly, B.L.E., Loo, L.C., and Lin, H.S. (2018). Pre-clinical pharmacokinetic and metabolomic analyses of isorhapontigenin, a dietary resveratrol derivative. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.00753"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2043","DOI":"10.1111\/bph.13803","article-title":"Isorhapontigenin, a bioavailable dietary polyphenol, suppresses airway epithelial cell inflammation through a corticosteroid independent mechanism","volume":"174","author":"Yeo","year":"2017","journal-title":"Br. J. Pharm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2664","DOI":"10.18632\/oncotarget.1872","article-title":"Isorhapontigenin (ISO) inhibited cell transformation by inducing G0\/G1 phase arrest via increasing MKP-1 mRNA Stability","volume":"5","author":"Gao","year":"2014","journal-title":"Oncotarget"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1002\/jcp.25968","article-title":"Isorhapontigenin induced cell growth inhibition and apoptosis by targeting EGFR-related pathways in prostate cancer","volume":"233","author":"Zhu","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.canlet.2021.07.041","article-title":"Isorhapontigenin (ISO) inhibits EMT through FOXO3A\/METTL14\/VIMENTIN pathway in bladder cancer cells","volume":"520","author":"Zhang","year":"2021","journal-title":"Cancer Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1038\/nature06030","article-title":"LKB1 modulates lung cancer differentiation and metastasis","volume":"448","author":"Ji","year":"2007","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"12859","DOI":"10.1073\/pnas.1405362111","article-title":"Nedd9 restrains renal cystogenesis in Pkd1 \u2212\/\u2212 mice","volume":"111","author":"Nikonova","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.gene.2015.04.086","article-title":"Preclinical and clinical studies of the NEDD9 scaffold protein in cancer and other diseases","volume":"567","author":"Shagisultanova","year":"2015","journal-title":"Gene"},{"key":"ref_15","first-page":"3","article-title":"Wnt\/\u03b2-catenin signaling: Function, biological mechanisms, and therapeutic opportunities. Signal Transduction","volume":"7","author":"Liu","year":"2022","journal-title":"Target. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"33972","DOI":"10.18632\/oncotarget.15687","article-title":"The regulation of \u03b2-Catenin activity and function in cancer: Therapeutic opportunities","volume":"8","author":"Shang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1038\/s41580-024-00823-y","article-title":"Mechanistic insights into Wnt\u2013\u03b2-catenin pathway activation and signal transduction","volume":"26","author":"Maurice","year":"2025","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2714","DOI":"10.1038\/emboj.2012.150","article-title":"The many faces and functions of \u03b2-catenin","volume":"31","author":"Valenta","year":"2012","journal-title":"EMBO J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2633","DOI":"10.1038\/onc.2010.632","article-title":"HEF1, a novel target of Wnt signaling, promotes colonic cell migration and cancer progress","volume":"30","author":"Li","year":"2011","journal-title":"Oncogene"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Lopes-Coelho, F., Martins, F., Pereira, S.A., and Serpa, J. (2021). Anti-Angiogenic Therapy: Current Challenges and Future Perspectives. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22073765"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/nm0295-149","article-title":"Dormancy of micrometastases: Balance proliferation and apoptosis in the presence of angiogenesis suppression","volume":"1","author":"Holmgren","year":"1995","journal-title":"Nat. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1002\/jcb.25074","article-title":"Regulation of hypoxia-inducible factor-1a by reactive oxygen species: New developments in an old debate","volume":"116","author":"Movafagh","year":"2015","journal-title":"J. Cell. Biochem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1016\/j.apsb.2015.05.007","article-title":"HIF-1\u03b1 pathway: Role, regulation and intervention for cancer therapy","volume":"5","author":"Masoud","year":"2015","journal-title":"Acta Pharm. Sin B"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Infantino, V., Santarsiero, A., Convertini, P., Todisco, S., and Iacobazzi, V. (2021). Cancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115703"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4054","DOI":"10.1158\/0008-5472.CAN-09-2110","article-title":"Human enhancer of filamentation 1 is a mediator of hypoxia-inducible factor-1alpha-mediated migration in colorectal carcinoma cells","volume":"70","author":"Kim","year":"2010","journal-title":"Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"11661","DOI":"10.1016\/j.taap.2023.116661","article-title":"Isorhapontigenin (ISO) inhibits malignant cell transformation, migration, and invasion through MEG3\/NEDD9 signaling in Cr(VI)-transformed cells","volume":"476","author":"Shi","year":"2023","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/s41392-023-01332-8","article-title":"Hypoxic microenvironment in cancer: Molecular mechanisms and therapeutic interventions","volume":"8","author":"Chen","year":"2023","journal-title":"Signal. Transduct. Target. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1038\/ncponc0342","article-title":"Angiogenic inhibitors: A new therapeutic strategy in oncology","volume":"2","author":"Gasparini","year":"2005","journal-title":"Nat. Rev. Pract. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1038\/s41392-023-01460-1","article-title":"Angiogenic signaling pathways and anti-angiogenic therapy for cancer","volume":"8","author":"Liu","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Saman, H., Raza, S.S., Uddin, S., and Rasul, K. (2020). Inducing Angiogenesis, a Key Step in Cancer Vascularization, and Treatment Approaches. Cancers, 12.","DOI":"10.20944\/preprints202004.0400.v1"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Tam, S.Y., Wu, V.W.C., and Law, H.K.W. (2020). Hypoxia-Induced Epithelial-Mesenchymal Transition in Cancers: HIF-1\u03b1 and Beyond. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.00486"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"8975","DOI":"10.1158\/0008-5472.CAN-07-1328","article-title":"A new central scaffold for metastasis: Parsing HEF1\/Cas-L\/NEDD9","volume":"67","author":"Seo","year":"2007","journal-title":"Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4854","DOI":"10.1038\/s41388-018-0296-y","article-title":"NEDD9 promotes oncogenic signaling, a stem\/mesenchymal gene signature, and aggressive ovarian cancer growth in mice","volume":"37","author":"Gabbasov","year":"2018","journal-title":"Oncogene"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Sima, N., Cheng, X., Ye, F., Ma, D., Xie, X., and L\u00fc, W. (2013). The Overexpression of Scaffolding Protein NEDD9 Promotes Migration and Invasion in Cervical Cancer via Tyrosine Phosphorylated FAK and SRC. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0074594"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"711","DOI":"10.2147\/OTT.S117933","article-title":"\u03b2-Catenin promotes cell proliferation, migration, and invasion but induces apoptosis in renal cell carcinoma","volume":"10","author":"Yang","year":"2017","journal-title":"Onco Targets Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e10086","DOI":"10.1016\/j.heliyon.2022.e10086","article-title":"Loss of MEG3 and upregulation of miR-145 play an important role in the invasion and migration of Cr(VI)-transformed cells","volume":"8","author":"Zhang","year":"2022","journal-title":"Heliyon"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"290","DOI":"10.4331\/wjbc.v6.i4.290","article-title":"Regulation of MYC gene expression by aberrant Wnt\/\u03b2-catenin signaling in colorectal cancer","volume":"6","author":"Rennoll","year":"2015","journal-title":"World J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5522","DOI":"10.1073\/pnas.96.10.5522","article-title":"The cyclin D1 gene is a target of the \u03b2-catenin\/LEF-1 pathway","volume":"96","author":"Shtutman","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","unstructured":"Non-small Cell Lung Cancer Collaborative Group (2000). Chemotherapy for non-small cell lung cancer. Cochrane Database Syst. Rev., 2000."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Chong, Y., Lee, H.L., Song, J., Lee, Y., Kim, B.G., Mok, H., and Ahn, J.H. (2021). Biosynthesis of resveratrol derivatives and evaluation of their anti-inflammatory activity. Appl. Biol. Chem., 64.","DOI":"10.1186\/s13765-021-00607-4"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e10122","DOI":"10.1016\/j.heliyon.2022.e10122","article-title":"Exploring flexibility, intermolecular interactions and ADMET profiles of anti-influenza agent isorhapontigenin: A quantum chemical and molecular docking study","volume":"8","author":"Bangaru","year":"2022","journal-title":"Heliyon"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1016\/j.apsb.2020.10.017","article-title":"Isorhapontigenin protects against doxorubicin-induced cardiotoxicity via increasing YAP1 expression","volume":"11","author":"Wang","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Sie, Y.Y., Chen, L.C., Li, C.J., Yuan, Y.H., Hsiao, S.H., Lee, M.H., Wang, C.C., and Hou, W.C. (2023). Inhibition of Acetylcholinesterase and Amyloid-\u03b2 Aggregation by Piceatannol and Analogs: Assessing In Vitro and In Vivo Impact on a Murine Model of Scopolamine-Induced Memory Impairment. Antioxidants, 12.","DOI":"10.3390\/antiox12071362"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1007\/s11255-022-03325-y","article-title":"Isorhapontigenin ameliorates high glucose-induced podocyte and vascular endothelial cell injuries via mitigating oxidative stress and autophagy through the AMPK\/Nrf2 pathway","volume":"55","author":"Tian","year":"2023","journal-title":"Int. Urol. Nephrol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"35234","DOI":"10.1074\/jbc.M112.389494","article-title":"The Chinese herb isolate isorhapontigenin induces apoptosis in human cancer cells by down-regulating overexpression of antiapoptotic protein XIAP","volume":"287","author":"Fang","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1016\/j.jid.2016.02.803","article-title":"Regulation of Melanoma Progression through the TCF4\/miR-125b\/NEDD9 Cascade","volume":"136","author":"Rambow","year":"2016","journal-title":"J. Investig. Dermatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1038\/nature03799","article-title":"Genes that mediate breast cancer metastasis to lung","volume":"436","author":"Minn","year":"2005","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"795","DOI":"10.3892\/etm.2012.693","article-title":"Role of NEDD9 in invasion and metastasis of lung adenocarcinoma","volume":"4","author":"Chang","year":"2012","journal-title":"Exp. Ther. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/onc.2012.632","article-title":"Aurora kinase A mediates epithelial ovarian cancer cell migration and adhesion","volume":"33","author":"Do","year":"2014","journal-title":"Oncogene"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/s41389-022-00391-w","article-title":"NEDD9 sustains hexokinase expression to promote glycolysis","volume":"11","author":"Deneka","year":"2022","journal-title":"Oncogenesis"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1126\/science.1059817","article-title":"HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: Implication for O2 sensing","volume":"292","author":"Ivan","year":"2001","journal-title":"Science"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/s41568-020-00307-z","article-title":"Mutations and mechanisms of WNT pathway tumour suppressors in cancer","volume":"21","author":"Bugter","year":"2021","journal-title":"Nat. Rev. Cancer"},{"key":"ref_53","first-page":"507","article-title":"Modulating \u03b2-catenin homeostasis for cancer therapy","volume":"10","author":"Xu","year":"2024","journal-title":"Trends Cancer"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3642","DOI":"10.1038\/onc.2009.224","article-title":"Nedd9\/Hef1\/Cas-L mediates the effects of environmental pollutants on cell migration and plasticity","volume":"28","author":"Bui","year":"2009","journal-title":"Oncogene"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Tikhmyanova, N., and Golemis, E.A. (2011). NEDD9 and BCAR1 negatively regulate E-cadherin membrane localization and promote E-cadherin degradation. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0022102"},{"key":"ref_56","first-page":"2307","article-title":"Loss of MEG3 contributes to the enhanced migration and invasion in arsenic-induced carcinogenesis through NQO1\/FSCN1 pathway","volume":"13","author":"Tu","year":"2023","journal-title":"Am. J. Cancer Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/9\/4207\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:23:47Z","timestamp":1760030627000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/9\/4207"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,29]]},"references-count":56,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["ijms26094207"],"URL":"https:\/\/doi.org\/10.3390\/ijms26094207","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,29]]}}}