Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy; Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy.
Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
Biochim Biophys Acta Rev Cancer. 2024 Jan;1879(1):189027. doi: 10.1016/j.bbcan.2023.189027. Epub 2023 Nov 24.
Endoplasmic reticulum oxidoreductin 1 (ERO1) alpha (ERO1A) is an endoplasmic reticulum (ER)-localized protein disulfide oxidoreductase, involved in the disulfide bond formation of proteins. ERO1's activity in oxidative protein folding is redundant in higher eukaryotes and its loss is well compensated. Although it is dispensable in non-cancer cells, high ERO1 levels are seen with different cancers and predict their malignant phenotype. ERO1 fosters tumor aggressiveness and the response to drug therapy in hypoxic and highly metastatic tumors. It regulates vascular endothelial growth factor (VEGF) levels, oxidative folding and N-glycosylation in hypoxic conditions, boosting tumor fitness and angiogenesis on multiple levels. In addition, ERO1 regulates protein death ligand-1 (PD-L1) on tumors, interfering with the related immune surveillance mechanism, hence acting on the tumors' response to immune check-point inhibitors (ICI). This all points to inhibition of ERO1 as an effective pharmacological tool, selectively targeting tumors while sparing non-cancer cells from cytotoxicity. The critical discussion here closely examines the molecular basis for ERO1's involvement in tumors and ERO1 inhibition strategies for their treatment.
内质网氧化还原酶 1（ERO1）α（ERO1A）是一种内质网（ER）定位的蛋白二硫键氧化还原酶，参与蛋白质中二硫键的形成。在高等真核生物中，ERO1 的氧化蛋白折叠活性是冗余的，其缺失可以得到很好的补偿。尽管在非癌细胞中ERO1 是可有可无的，但在不同的癌症中可以看到高水平的 ERO1，并预测其恶性表型。ERO1 在缺氧和高转移性肿瘤中促进肿瘤侵袭性和对药物治疗的反应。它在缺氧条件下调节血管内皮生长因子（VEGF）水平、氧化折叠和 N-糖基化，在多个层面上提高肿瘤的适应性和血管生成能力。此外，ERO1 调节肿瘤上的蛋白死亡配体-1（PD-L1），干扰相关的免疫监视机制，从而影响肿瘤对免疫检查点抑制剂（ICI）的反应。所有这些都表明抑制 ERO1 是一种有效的药理学工具，可以选择性地靶向肿瘤，同时使非癌细胞免受细胞毒性。这里的批判性讨论密切检查了 ERO1 参与肿瘤的分子基础以及 ERO1 抑制策略在肿瘤治疗中的应用。
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