Abstract
Abstract The commonly used immunosuppressant cyclosporin A (CsA), 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 CsA treatment. Despite the significance of calcineurin signaling in endothelial cells, the consequences of CsA on tumor angiogenesis has not been investigated. Using an in vivo model of skin carcinogenesis, we show that long-term CsA treatment promotes tumor growth and angiogenesis. Treatment of endothelial cells in vitro with CsA increases proliferation and migration in a calcineurin-independent manner and is associated with increased mitochondrial reactive oxygen species. Co-treatment with antioxidants significantly abrogated CsA-induced endothelial cell activation. Furthermore, mice treated with antioxidants were protected against CsA-mediated tumor progression. Taken together, these findings show that CsA functions independent of calcineurin to potentiate tumor growth by promoting tumor angiogenesis via mitochondrial reactive oxygen species production. This work identifies a previously undescribed mechanism underlying a significantly adverse off-target effect of CsA and suggests that co-treatment with antioxidants may inhibit the tumor promoting effects of CsA. Citation Format: Alice Yao Zhou, Sandra W. Ryeom. Cyclosporin A promotes tumor angiogenesis in a calcineurin-independent manner by increasing mitochondrial reactive oxygen species. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A11. doi:10.1158/1538-7445.CHTME14-A11
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