Frontiers in immunology · 2026
p53-associated regulation of COX17 enhances elesclomol-induced copper-associated cytotoxicity and suppresses gastric cancer growth.
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Li Qianling, Dong Xiaoyin, Zhao Yu, Shen Yun, Yang Chenyang, Xi Yu
Аннотация
BACKGROUND: 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.
METHODS: 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. In vivo relevance was examined in a subcutaneous AGS xenograft model treated with elesclomol.
RESULTS: 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.
CONCLUSION: These findings suggest that the p53-COX17 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.
METHODS: 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. In vivo relevance was examined in a subcutaneous AGS xenograft model treated with elesclomol.
RESULTS: 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.
CONCLUSION: These findings suggest that the p53-COX17 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.