{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T05:55:04Z","timestamp":1781502904632,"version":"3.54.1"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cuproptosis is a copper-dependent form of regulated cell death with emerging relevance to cancer therapy. However, the upstream determinants of copper-associated cytotoxicity and cuproptosis-related sensitivity in gastric cancer remain incompletely defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Using AGS gastric cancer cells with genetic gain- and loss-of-function of COX17 and p53, we assessed viability using CCK-8 assays, cell death using TUNEL staining, intracellular copper levels, migration and invasion using wound healing and Transwell assays, and the expression of copper handling and cuproptosis-associated proteins by Western blotting. The potential transcriptional regulation of COX17 by p53 was evaluated using ChIP-qPCR. Paracrine effects on angiogenesis-related phenotypes were evaluated in HUVECs exposed to tumor-cell-conditioned media, followed by tube formation, ROS, GSH, SOD, and MDA measurements.\n                      <jats:italic>In vivo<\/jats:italic>\n                      relevance was examined in a subcutaneous AGS xenograft model treated with elesclomol.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>COX17 alone had only a modest effect on basal cell viability but markedly increased the sensitivity of AGS cells to elesclomol-induced copper-associated cytotoxicity, accompanied by increased intracellular copper accumulation and TUNEL positivity, whereas COX17 knockdown attenuated these effects. Elesclomol treatment with COX17 modulation was associated with increased SLC31A1 expression and decreased ATP7A expression. p53 overexpression suppressed malignant phenotypes and increased COX17 expression. ChIP-qPCR showed the enrichment of p53 at the COX17 promoter region, suggesting that p53 may participate in the transcriptional regulation of COX17. Functional rescue experiments further indicated that COX17 is an important downstream mediator of p53-associated sensitivity to elesclomol. Conditioned media from elesclomol-treated, COX17-overexpressing tumor cells inhibited HUVEC tube formation and proliferation and increased oxidative stress. In xenografts, elesclomol reduced tumor growth, which was further suppressed by COX17 overexpression and partially attenuated by COX17 silencing, accompanied by increased tumor copper accumulation, upregulation of p53\/COX17\/SLC31A1, and downregulation of ATP7A.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings suggest that the p53\u2013COX17 axis links copper metabolism to elesclomol-associated antitumor activity in gastric cancer. COX17 may enhance copper accumulation, oxidative stress, tumor-cell-death-associated changes, and angiogenesis-related phenotypic inhibition. Further studies using canonical cuproptosis markers, copper chelator rescue experiments, additional gastric cancer cell lines with different p53 backgrounds, and clinical validation are required to confirm the translational significance of this pathway.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1817305","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T05:33:15Z","timestamp":1781501595000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["p53-associated regulation of COX17 enhances elesclomol-induced copper-associated cytotoxicity and suppresses gastric cancer growth"],"prefix":"10.3389","volume":"17","author":[{"given":"Qianling","family":"Li","sequence":"first","affiliation":[{"name":"The First Affiliated Hospital of Shihezi University","place":["Shihezi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyin","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shihezi University","place":["Shihezi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shihezi University","place":["Shihezi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Shihezi University","place":["Shihezi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyang","family":"Yang","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Shihezi University","place":["Shihezi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Xi","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shihezi University","place":["Shihezi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/b978-0-443-15609-0.00017-9","article-title":"Gastric cancer","volume":"396","author":"Smyth","year":"2020","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1159\/000506509","article-title":"Gastric cancer: Where are we heading","volume":"38","author":"Petryszyn","year":"2020","journal-title":"Dig Dis"},{"key":"B3","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.suc.2024.06.006","article-title":"Treatment of early gastric cancer","volume":"105","author":"Liu-Burdowski","year":"2025","journal-title":"Surg Clin North Am"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21657","article-title":"Current treatment and recent progress in gastric cancer","volume":"71","author":"Joshi","year":"2021","journal-title":"CA Cancer J Clin"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2024.03.008","article-title":"Gastric cancer immunosuppressive microenvironment heterogeneity: Implications for therapy development","volume":"10","author":"Yasuda","year":"2024","journal-title":"Trends Cancer"},{"key":"B6","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1038\/s41388-022-02537-x","article-title":"Cst1 inhibits ferroptosis and promotes gastric cancer metastasis by regulating Gpx4 protein stability via Otub1","volume":"42","author":"Li","year":"2023","journal-title":"Oncogene"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-020-01168-8","article-title":"Caf secreted Mir-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer","volume":"19","author":"Zhang","year":"2020","journal-title":"Mol Cancer"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1435651","article-title":"The role of cuproptosis in gastric cancer","volume":"15","author":"Li","year":"2024","journal-title":"Front Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1126\/science.abo3959","article-title":"Copper-induced cell death","volume":"375","author":"Kahlson","year":"2022","journal-title":"Science"},{"key":"B10","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1038\/s41392-025-02192-0","article-title":"The molecular mechanism and therapeutic landscape of copper and cuproptosis in cancer","volume":"10","author":"Guo","year":"2025","journal-title":"Signal Transduct Target Ther"},{"key":"B11","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1002\/cac2.70005","article-title":"Copper in cancer: Friend or foe? Metabolism, dysregulation, and therapeutic opportunities","volume":"45","author":"Shan","year":"2025","journal-title":"Cancer Commun (Lond)"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2023.122223","article-title":"Copper homeostasis and cuproptosis in mitochondria","volume":"334","author":"Tian","year":"2023","journal-title":"Life Sci"},{"key":"B13","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1186\/s13046-023-02720-2","article-title":"Ferroptosis inducers enhanced cuproptosis induced by copper ionophores in primary liver cancer","volume":"42","author":"Wang","year":"2023","journal-title":"J Exp Clin Cancer Res"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3390\/biom12020327","article-title":"Regulation of P53 function by formation of non-nuclear heterologous protein complexes","volume":"12","author":"Zavileyskiy","year":"2022","journal-title":"Biomolecules"},{"key":"B15","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1186\/s13287-025-04653-3","article-title":"Mscs-derived Hgf alleviates senescence after Aki by modulating Mitostat3-controlled copper flux and respiration","volume":"16","author":"Zhuang","year":"2025","journal-title":"Stem Cell Res Ther"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2023.2200554","article-title":"Copper metabolism in cell death and autophagy","volume":"19","author":"Xue","year":"2023","journal-title":"Autophagy"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2023.102990","article-title":"Lead aggravates Alzheimer's disease pathology via mitochondrial copper accumulation regulated by Cox17","volume":"69","author":"Huang","year":"2024","journal-title":"Redox Biol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1186\/s13045-024-01589-8","article-title":"Targeting cuproptosis for cancer therapy: Mechanistic insights and clinical perspectives","volume":"17","author":"Zhang","year":"2024","journal-title":"J Hematol Oncol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.114301","article-title":"4-Octyl itaconate inhibits aerobic glycolysis by targeting Gapdh to promote cuproptosis in colorectal cancer","volume":"159","author":"Yang","year":"2023","journal-title":"BioMed Pharmacother"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.775312","article-title":"The basally expressed P53-mediated homeostatic function","volume":"9","author":"Nagpal","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202200829r","article-title":"Zebrafish Cox17 modulates primitive erythropoiesis via regulation of mitochondrial metabolism to facilitate hypoxia tolerance","volume":"36","author":"Li","year":"2022","journal-title":"FASEB J"},{"key":"B22","doi-asserted-by":"publisher","first-page":"7311","DOI":"10.1038\/s41467-021-27559-z","article-title":"Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis","volume":"12","author":"Ramchandani","year":"2021","journal-title":"Nat Commun"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.14712\/fb2019065040181","article-title":"Stable Cox17 downregulation leads to alterations in mitochondrial ultrastructure, decreased copper content and impaired cytochrome C oxidase biogenesis in Hek293 cells","volume":"65","author":"Vani\u0161ov\u00e1","year":"2019","journal-title":"Folia Biol (Praha)"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf0529","article-title":"Copper induces cell death by targeting lipoylated Tca cycle proteins","volume":"375","author":"Tsvetkov","year":"2022","journal-title":"Science"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1126\/science.1126863","article-title":"P53 regulates mitochondrial respiration","volume":"312","author":"Matoba","year":"2006","journal-title":"Science"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2022.113249","article-title":"P53 regulates mitochondrial biogenesis via transcriptionally induction of mitochondrial ribosomal protein L12","volume":"418","author":"Han","year":"2022","journal-title":"Exp Cell Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-023-01098-3","article-title":"Cox17 restricts renal fibrosis development by maintaining mitochondrial copper homeostasis and restoring complex Iv activity","volume":"44","author":"Zhu","year":"2023","journal-title":"Acta Pharmacol Sin"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2011.530","article-title":"Synthesis of cytochrome C oxidase 2: A P53-dependent metabolic regulator that promotes respiratory function and protects glioma and colon cancer cells from hypoxia-induced cell death","volume":"31","author":"Wanka","year":"2012","journal-title":"Oncogene"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1093\/mtomcs\/mfaf025","article-title":"The relationship between copper metabolism and P53 activity in tumors","volume":"17","author":"Yu","year":"2025","journal-title":"Metallomics"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2023.07.022","article-title":"P53 at the crossroad between mitochondrial reactive oxygen species and necroptosis","volume":"207","author":"Rius-P\u00e9rez","year":"2023","journal-title":"Free Radic Biol Med"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1002\/iub.1618","article-title":"Copper metallothioneins","volume":"69","author":"Calvo","year":"2017","journal-title":"IUBMB Life"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.envint.2023.108237","article-title":"Bap\/Bpde suppressed endothelial cell angiogenesis to induce miscarriage by promoting Marchf1\/Gpx4-mediated ferroptosis","volume":"180","author":"Zhang","year":"2023","journal-title":"Environ Int"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioactmat.2024.09.006","article-title":"Mmp-9 responsive hydrogel promotes diabetic wound healing by suppressing ferroptosis of endothelial cells","volume":"43","author":"Lin","year":"2025","journal-title":"Bioact Mater"},{"key":"B34","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1093\/cvr\/cvae270","article-title":"Iron, lipid peroxidation, and ferroptosis play pathogenic roles in atherosclerosis","volume":"121","author":"Jinson","year":"2025","journal-title":"Cardiovasc Res"},{"key":"B35","doi-asserted-by":"publisher","first-page":"597","DOI":"10.2217\/nnm-2023-0301","article-title":"Copper oxide nanoparticles suppress retinal angiogenesis via inducing endothelial cell cuproptosis","volume":"19","author":"Zhang","year":"2024","journal-title":"Nanomedicine (Lond)"},{"key":"B36","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1186\/s12964-024-01726-3","article-title":"The crosstalk between copper-induced oxidative stress and cuproptosis: A novel potential anticancer paradigm","volume":"22","author":"Vo","year":"2024","journal-title":"Cell Commun Signal"},{"key":"B37","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1186\/s12943-024-02130-8","article-title":"Cuproptosis, ferroptosis and panoptosis in tumor immune microenvironment remodeling and immunotherapy: Culprits or new hope","volume":"23","author":"Zhang","year":"2024","journal-title":"Mol Cancer"},{"key":"B38","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/j.molcel.2024.11.013","article-title":"P53 induces Circfrmd4a to suppress cancer development through glycolytic reprogramming and cuproptosis","volume":"85","author":"Liao","year":"2025","journal-title":"Mol Cell"},{"key":"B39","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1038\/s41392-022-01014-x","article-title":"Cuproptosis: Lipoylated Tca cycle proteins-mediated novel cell death pathway","volume":"7","author":"Li","year":"2022","journal-title":"Signal Transduct Target Ther"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.vph.2020.106762","article-title":"4-Hydroxy-2-nonenal decreases coronary endothelial cell migration: Potentiation by aldehyde dehydrogenase 2 inhibition","volume":"131","author":"Roy","year":"2020","journal-title":"Vascul Pharmacol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1817305\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T05:33:15Z","timestamp":1781501595000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1817305\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,15]]},"references-count":40,"alternative-id":["10.3389\/fimmu.2026.1817305"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1817305","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,15]]},"article-number":"1817305"}}