Activation of calcineurin in cancer: many paths, one hub

Calcineurin is a calcium dependent serine/threonine phosphatase that integrates changes in intracellular calcium with downstream signaling pathways. A recent paper by Peuker et al. published in Nature Medicine identifies calcineurin as a key mediator of tumor growth and proliferation in response to altered stratification of the microbiota. Peuker et al. show that alterations in microbiota stratification activate toll-like receptor (TLR) signaling, which in turn activates calcineurin-NFAT signaling. While this is the first example of calcineurin activation in cancer through the intestinal microbiota, calcineurin is increasingly being recognized as a commonly activated target in cancer. Increases in intracellular calcium in response to hypoxic conditions, inflammation, and vascular endothelial growth factor signaling have all been demonstrated to result in increased calcineurin activation in malignant cells. More recently, cleavage of calcineurin has been associated with increased activity in cancer. Activation of calcineurin is implicated in signaling pathways promoting proliferation, migration, and metastasis. The elevated frequency of calcineurin activation in cancer highlights the importance of this pathway as a potential therapeutic target.