Zhou Alice Yao, Ryeom Sandra
Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
Mol Cancer Res. 2014 Nov;12(11):1663-76. doi: 10.1158/1541-7786.MCR-14-0136. Epub 2014 Jul 9.
The widely used immunosuppressant cyclosporin A, a potent calcineurin inhibitor, significantly increases the incidence of cancer in organ transplant patients. Calcineurin signaling is an important mediator of VEGF signaling in endothelial cells. Negative regulation of calcineurin by its endogenous inhibitor, Down Syndrome Candidate Region-1 (DSCR1), suppresses tumor growth and angiogenesis, in contrast to the effect observed after long-term cyclosporin A treatment. Despite the significance of calcineurin signaling in endothelial cells, the consequences of cyclosporin A on tumor angiogenesis have not been investigated. Using an in vivo model of skin carcinogenesis, prolonged treatment with cyclosporin A promoted tumor growth and angiogenesis. The addition of cyclosporin A to endothelial cells in vitro increased proliferation and migration in a calcineurin-independent manner and is associated with increased mitochondrial reactive oxygen species (ROS). Co-treatment with antioxidants significantly abrogated cyclosporin A-induced endothelial cell activation. Furthermore, mice treated with antioxidants were protected against cyclosporin A-mediated tumor progression. Taken together, these findings suggest that cyclosporin A affects endothelial cells in a calcineurin-independent manner to potentiate tumor growth by promoting tumor angiogenesis through increasing mitochondrial ROS production. This work identifies a previously undescribed mechanism underlying a significantly adverse off-target effect of cyclosporin A and suggests that co-treatment with antioxidants would inhibit the tumor-promoting effects of cyclosporin A.
Targeting the proangiogenic effects of cyclosporin A may be useful in the management of transplant-associated cancers.
广泛使用的免疫抑制剂环孢素A是一种有效的钙调神经磷酸酶抑制剂，它会显著增加器官移植患者患癌的几率。钙调神经磷酸酶信号传导是内皮细胞中血管内皮生长因子（VEGF）信号传导的重要介质。其内源性抑制剂唐氏综合征候选区域-1（DSCR1）对钙调神经磷酸酶的负调控可抑制肿瘤生长和血管生成，这与长期使用环孢素A治疗后观察到的效果相反。尽管钙调神经磷酸酶信号传导在内皮细胞中具有重要意义，但环孢素A对肿瘤血管生成的影响尚未得到研究。使用皮肤癌发生的体内模型，长期使用环孢素A治疗可促进肿瘤生长和血管生成。在体外向内皮细胞中添加环孢素A以不依赖钙调神经磷酸酶的方式增加细胞增殖和迁移，并与线粒体活性氧（ROS）增加有关。与抗氧化剂共同处理可显著消除环孢素A诱导的内皮细胞活化。此外，用抗氧化剂处理的小鼠可免受环孢素A介导的肿瘤进展的影响。综上所述，这些发现表明，环孢素A以不依赖钙调神经磷酸酶的方式影响内皮细胞，通过增加线粒体ROS生成促进肿瘤血管生成，从而增强肿瘤生长。这项工作确定了环孢素A显著不良脱靶效应背后一种先前未描述的机制，并表明与抗氧化剂共同处理可抑制环孢素A的促肿瘤作用。
针对环孢素A的促血管生成作用可能有助于管理移植相关癌症。
