| First Author | Zhou AY | Year | 2014 |
| Journal | Mol Cancer Res | Volume | 12 |
| Issue | 11 | Pages | 1663-76 |
| PubMed ID | 25009293 | Mgi Jnum | J:216706 |
| Mgi Id | MGI:5609236 | Doi | 10.1158/1541-7786.MCR-14-0136 |
| Citation | Zhou AY, et al. (2014) Cyclosporin a promotes tumor angiogenesis in a calcineurin-independent manner by increasing mitochondrial reactive oxygen species. Mol Cancer Res 12(11):1663-76 |
| abstractText | 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. IMPLICATIONS: Targeting the proangiogenic effects of cyclosporin A may be useful in the management of transplant-associated cancers. |
