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Activation of Calcineurin in Cancer: Many Paths, One Hub

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Activation of Calcineurin in Cancer: Many Paths, One Hub Perspective Activation of calcineurin in cancer: many paths, one hub Miranda Brun, Roseline Godbout Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Canada Correspondence to: Roseline Godbout. Department of Oncology, 11560 University Avenue, Edmonton, Alberta Canada T6G 1Z2, Canada. Email: [email protected]. Comment on: Peuker K, Muff S, Wang J, et al. Epithelial calcineurin controls microbiota-dependent intestinal tumor development. Nat Med 2016;22:506-15. Abstract: 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. Keywords: Calcineurin; cancer; cleavage; microbiota; phosphatase Submitted Jul 30, 2016. Accepted for publication Aug 09, 2016. doi: 10.21037/tcr.2016.09.30 View this article at: http://dx.doi.org/10.21037/tcr.2016.09.30 Introduction plays a central role in immunity, as demonstrated by the use of calcineurin inhibitors cyclosporine A and tacrolimus Colorectal cancer is the third most diagnosed cancer and (FK506) as immunosuppressants (7). the fourth leading cause of cancer-related death worldwide, Calcineurin is composed of two subunits, a catalytic and the second leading cause of cancer-related deaths in subunit called calcineurin A (CNA) encoded by three developed countries (1). The worldwide incidence of colon separate genes (PPP3CA, PPP3CB and PPP3CC), and a cancer is predicted to rise by 60% within 15 years, in line regulatory subunit, calcineurin B (CNB; Cnb) encoded with observations linking increased colon cancer incidence by two genes, PPP3R1 and PPP3R2, with the latter with increased industrial development (2). Intestinal restricted to testis and brain. In the presence of elevated inflammation is a risk factor for colorectal cancer: with calcium, calmodulin binds to calcineurin, displacing the inflammatory bowel disease significantly increasing the risk autoinhibitory domain from the active site, leading to of colitis-associated colorectal cancer (3). Inflammatory activation of calcineurin and subsequent dephosphorylation signaling through STAT3 and NF-κB is also activated of target proteins. Calcineurin substrates include in colorectal tumors and cell lines (4,5). In their recent transcription factors, proteins involved in cell cycle publication, Peuker et al. (6) identify calcineurin as a and apoptosis, cytoskeletal proteins, scaffold proteins, promoter of colorectal cancer growth through maintenance membrane channels and receptors (Table 1) (10). and proliferation of cancer stem cells. Calcineurin is a The best characterized calcineurin substrates are the calcium dependent serine/threonine phosphatase that nuclear factor of activated T cells (NFAT) transcription © Translational Cancer Research. All rights reserved. tcr.amegroups.com Transl Cancer Res 2016;5(S3):S497-S506 S498 Brun and Godbout. Activation of calcineurin in cancer Table 1 Targets of calcineurin dephosphorylation in both a genetic model and a colitis-associated model of colorectal cancer. By specifically deleting the regulatory Category Target B1 subunit of calcineurin (Cnb1, encoded by Ppp3r1) in Transcription factors/transcriptional c-Jun (8) the intestinal epithelial cells of the ApcMin/+ mouse model regulation DAXX (9) of colon cancer, they observe both fewer and smaller Elk-1 (10) intestinal tumors. Similar results were obtained when mice carrying intestinal epithelial cell-specific deletion of Hcm1 (11) Ppp3r1 were treated with colitis-inducing dextran sulfate MEF2 (12) along with the carcinogen azoxymethane. In particular, the NFAT (13) authors noted that early stage lesions were reduced in their NFI (14) colorectal cancer models, and that the early lesions showed reduced epithelial proliferation and increased apoptosis. TFEB (15) Peuker et al. (6) further showed that NFATc3 is the main Cytoskeleton MAP2 (16) NFAT expressed in normal intestinal epithelial cells, and Tubulin (16) that tumor formation is accompanied by calcineurin- dependent cytoplasmic to nuclear translocation of NFATc3. Tau (16) Intestinal epithelial cell-specific deletion of NFATc3 Cell cycle/apoptosis BAD (17) resulted in a phenotype similar to that of Ppp3r1−/− mice, pRb (18) albeit attenuated. The full phenotype was restored upon Min/+ Drp1 (10) treatment of Apc mice with a peptide that interferes with calcineurin-dependent activation of all NFATs. Scaffold proteins KSR2 (19) DARP-32 (10) Calcineurin in stem cell proliferation and RACK1 (10) differentiation Synapsin (20) The intestinal epithelium is maintained by continuous GAP43 (20) renewal through a tightly regulated balance of intestinal Ion channels/membrane channels GluA1 receptor (20) stem cell proliferation and differentiation. In Drosophila, NMDA receptor (20) high cytoplasmic calcium concentration results in activation of calcineurin and downstream targets, triggering GABA(A) receptor (20) proliferation of intestinal stem cells (22). Silencing of either mGluR5 (20) the regulatory subunit of calcineurin CanB2 or the catalytic Kv4.2 (20) subunit of calcineurin CanA1 in Drosophila significantly TRESK (10) reduces stem cell proliferation, highlighting a crucial role for calcineurin in translating changes in calcium signaling to proliferation of intestinal stem cells. Paradoxically, in addition to a role in cell proliferation, factors. Four of the five members of the NFAT protein calcineurin also promotes differentiation. Calcineurin- family are regulated by calcium signaling: NFATc1 NFAT signaling is necessary for lineage specification in (NFAT2), NFATc2 (NFAT1), NFATc3 (NFAT4), and embryonic stem cells, triggering the transition of these NFATc4 (NFAT3). In resting cells, NFAT is highly stem cells from self-renewal to differentiation (23). phosphorylated which precludes exposure of a nuclear Calcineurin-NFAT signaling also initiates skeletal muscle localization sequence (21). Following dephosphorylation differentiation (24), alveolar specification of adult lung by calcineurin, NFAT is translocated to the nucleus where stem cells (25), terminal differentiation of osteoclasts (26), it regulates gene expression, including genes encoding and stem cell quiescence in keratinocytes (27). In the cytokines in immune cells. cardiovascular system, calcineurin is important for Peuker et al. (6) examine the contribution of calcineurin cardiomyocyte maturation, valve formation, and vascular and its downstream target NFAT to intestinal tumor growth development. Loss of calcineurin results in heart defects © Translational Cancer Research. All rights reserved. tcr.amegroups.com Transl Cancer Res 2016;5(S3):S497-S506 Translational Cancer Research, Vol 5, Suppl 3 September 2016 S499 and reduced proliferation, whereas calcineurin is necessary decreases cancer stem cell survival and proliferation for hypertrophic response in adult cardiomyocytes (6,44). Similarly, calcineurin is activated in breast cancer, (28,29). In the brain, calcineurin is highly expressed in specifically in triple negative breast cancer, and promotes neurons, and plays an important role in the modulation migration and invasion in vitro and growth and metastasis of synaptic transmission (20). Calcineurin activity is also in vivo (45,46). Analogous findings by others support a pro- required for neural induction in the developing embryo tumorigenic role for calcineurin signaling in lung, prostate, through dephosphorylation and inactivation of Smad1/5 bladder, ovarian, pancreatic, and liver cancer, as well as to antagonize signaling through the bone morphogenetic glioblastoma, melanoma and leukemia (14,47-55). protein (BMP) (30). Studies addressing calcineurin activation have focused The immunosuppressive activity of the calcineurin principally on dephosphorylation and activation of NFAT inhibitor cyclosporine A was first described in 1976, and NFAT transcriptional targets. NFAT in and of itself and calcineurin inhibitors have been widely used as is constitutively activated or overexpressed in numerous immunosuppressants since the mid-80’s (31). The study of cancers and can contribute to cancer development and calcineurin inhibitors revealed a vital role for calcineurin progression (56). Additional calcineurin substrates including in regulating T cell development and activation through myocyte enhancer factor 2 (MEF2), kinase suppressor of ras the NFAT family (32-34). In T cells, binding of the T-cell 2 (KSR2), DAXX, c-Jun
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