Cyclosporin A Promotes Tumor Angiogenesis in a Calcineurin-Independent Manner by Increasing Mitochondrial Reactive Oxygen Species

Abstract

The widely 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, prolonged treatment with CsA promoted tumor growth and angiogenesis. The addition of CsA 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 CsA-induced endothelial cell activation. Furthermore, mice treated with antioxidants were protected against CsA-mediated tumor progression. Taken together, these findings suggest that CsA 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 CsA and suggests that co-treatment with antioxidants would inhibit the tumor promoting effects of CsA.

Survival after a cancer diagnosis among solid organ transplant recipients in the United States

“…27 Finally, immunosuppressive drugs may directly contribute to cancer-specific mortality among transplant recipients by promoting tumor invasiveness, angiogenesis, and metastasis. [5][6][7] The emerging understanding of how TILs and immunotherapy influence prognosis among patients with the aforementioned cancers makes the strong associations for melanoma, bladder cancer, breast cancer, and CRC more intriguing. Moreover, in the study by Shiels et al, 16 patients with melanoma and bladder cancer presented at more distant stages of disease among both transplant recipients and HIV-infected individuals than patients with cancer in the general population.…”

“…In particular, heightened immune function as reflected by the presence of tumor-infiltrating lymphocytes (TILs) is associated with lower mortality in patients with melanoma, 17 CRC, 18,19 bladder cancer, 20 and breast cancer, [21][22][23] and with favorable tumor features, such the absence of lymph node metastases in patients with melanoma 24 and chemotherapeutic response in individuals with breast cancer. [5][6][7] The emerging understanding of how TILs and immunotherapy influence prognosis among patients with the aforementioned cancers makes the strong associations for melanoma, bladder cancer, breast cancer, and CRC more intriguing. In addition, immunotherapy, in particular monoclonal antibodies that target programmed death-ligand 1 and its receptor programmed cell death protein 1 on T cells, is increasingly being used to manage patients with advanced stage cancers, including melanoma, bladder cancer, and lung cancer.…”

“…1 Although solid organ transplantation is life-saving, recipients have an elevated risk of many cancer types. [5][6][7] If immunosuppression affects cancer outcomes, it could be reasoned that transplant recipients with cancer also would have higher cancer-specific mortality compared with patients with cancer who have not undergone transplantation, although to the best of our knowledge the evidence to date is limited. In addition, some medications given after transplantation may be inherently carcinogenic or promote tumor growth.…”

“…In addition, some medications given after transplantation may be inherently carcinogenic or promote tumor growth. [5][6][7] If immunosuppression affects cancer outcomes, it could be reasoned that transplant recipients with cancer also would have higher cancer-specific mortality compared with patients with cancer who have not undergone transplantation, although to the best of our knowledge the evidence to date is limited. 8,9 Several factors may contribute to mortality differences between transplant recipients and others who develop cancer.…”

The critical role of calcineurin/NFAT (C/N) pathways and effective antitumor prospect for colorectal cancers

“…In addition, cell transformation is lined with other signaling pathway associated such as nutrition‐sensing phosphatidylinositol 3 kinase (PI3K)/mammalian target of rapamyein (mTOR) and glycogen synthase kinase 3 (GSK‐3) activities, which were demonstrated via the phosphorylation and regulation of NFAT activity, while GSK‐3 activity may inhibit mTOR or AKT . In fact, mTOR inhibitor (rapamycin) can inhibit the two forms of mTOR, viz, raptor (mTORC1) and rictor (mTORC2) complexes . These observations may help to improve the inhibition of NFAT antitumor activity and the possibility of tumor growth, including deregulation of PI3K‐mTOR pathway activation.…”