Cyclosporin A inhibits colon cancer cell growth independently of the calcineurin pathway

Werneck, Miriam B. F.; Hottz, Eugênio D.; Bozza, Patrı́cia T.; Viola, João P. B.

doi:10.4161/cc.22222

Cited by 34 publications

(22 citation statements)

References 49 publications

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“…Previous epidemiologic studies have reported the increased risk in the incidence of colorectal cancer among patients receiving calcineurin inhibitors as immunosuppressants, probably due to an impaired calcineurin-dependent tumor immunosurveillance (40,41). Moreover, a previous report suggested that FK506 promotes colorectal cancer cell line growth, although cyclosporin A inhibits the tumor growth independent of the calcineurin pathway (38). In contrast, several reports have indicated that calcineurin and NFAT have oncogenic functions, and blocking them inhibits colorectal cancer cell growth (26,42).…”

Section: Discussionmentioning

confidence: 80%

“…The effect of calcineurin in colorectal cancer remains controversial, and calcineurin may act as both a tumor suppressor while also inducing oncogenic activity in colorectal cancer (26,38,39). Previous epidemiologic studies have reported the increased risk in the incidence of colorectal cancer among patients receiving calcineurin inhibitors as immunosuppressants, probably due to an impaired calcineurin-dependent tumor immunosurveillance (40,41).…”

Section: Discussionmentioning

confidence: 99%

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The Tissue-Reconstructing Ability of Colon CSCs Is Enhanced by FK506 and Suppressed by GSK3 Inhibition

Ishida

Koyanagi-Aoi

Oshima

et al. 2017

Molecular Cancer Research

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Cancer stem cells (CSC) are capable of reconstructing cancer tissues, are involved in both recurrence and metastasis, and contribute to therapeutic resistance. Therefore, elucidating the molecular mechanism in CSCs is important to successfully treat unresectable cancers. Previously, we observed that colon cancer stem-like cells can be induced from human colon cancer cell lines by retrovirally introducing OCT3/4, SOX2, and KLF4, and we have designated such cells as induced cancer stem cells (iCSC). In the current study, we used iCSCs to evaluate the molecular mechanism of colon CSCs and developed new methods to control them. The spheres that were derived in vitro from the iCSCs, but not those from parental cells, mimicked human colon cancer tissues in terms of their immunohistologic patterns; therefore, sphere-forming ability was assessed as a measure of the tissuereconstructing ability of iCSCs. Interestingly, the calcineurin inhibitor FK506 enhanced the sphere-forming ability of iCSCs, whereas GSK3 inhibition by RNAi, CHIR99021, and valproic acid (VPA) impeded the sphere-forming ability and expansion of iCSCs. FK506 and GSK3 inhibition showed the opposite effect regarding the NFATc3 localization of iCSCs. These data reveal the crucial role that NFAT localization, as regulated by calcineurin and GSK3, plays in the tissue-reconstructing ability of colon cancer stem cells and the potential of GSK3 inhibitors, such as VPA, in colon cancer stem cell-targeting therapy.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

The Tissue-Reconstructing Ability of Colon CSCs Is Enhanced by FK506 and Suppressed by GSK3 Inhibition

Ishida

Koyanagi-Aoi

Oshima

et al. 2017

Molecular Cancer Research

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“…2, NFATc1 and especially NFAT5 were highly expressed in PASMCs, but the roles of these proteins remain unclear. In addition, some researchers are of the opinion that CsA affects cell apoptosis in an NFAT-independent manner or by decreasing STAT3/NF-κB activation [53,54]. It is well known that NFAT is the most important substrate of CaN.…”

Section: Discussionmentioning

confidence: 99%

Calcineurin/NFAT Signaling Modulates Pulmonary Artery Smooth Muscle Cell Proliferation, Migration and Apoptosis in Monocrotaline-Induced Pulmonary Arterial Hypertension Rats

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Pulmonary arterial hypertension (PAH) is a severe and debilitating disease characterized by remodeling of the pulmonary vessels, which is driven by excessive proliferation and migration and apoptosis resistance in pulmonary artery smooth muscle cells (PASMCs). The calcineurin (CaN)/nuclear factor of activated T-cells (NFAT) signaling pathway is the most important downstream signaling pathway of store-operated Ca²⁺ entry (SOCE), which is increased in PAH. CaN/NFAT has been reported to contribute to abnormal proliferation in chronic hypoxia (CH)-induced PAH. However, the effect of CaN/NFAT signaling on PASMC proliferation, migration and apoptosis in monocrotaline (MCT)-induced PAH remains unclear. Methods: PAH rats were established by a single intraperitoneal injection of MCT for 21 days. PASMCs were isolated and cultured in normal and MCT-induced PAH Sprague-Dawley rat. PASMCs were treated with CsA targeting CaN and siRNA targeting NFATc2-4 gene respectively by liposome. We investigated the expression of calcineurin/NFAT signaling by immunofluorescence, qRT-PCR and Western blotting methods. Cell proliferation was monitored using MTS reagent or by assessing proliferating cell nuclear antigen (PCNA) expression. Cell apoptosis was evaluated with an Annexin V - FITC/propidium iodide (PI) apoptosis kit by flow cytometry. PASMC migration was assessed with a Transwell chamber. Results: MCT successfully induced PAH and pulmonary vascular remodeling in rats. CaN phosphatase activity and nuclear translocation of NFATc2-4 were increased in PASMCs derived from MCT-treated rats. In addition, CaNBβ/NFATc2-4 expression was amplified at the mRNA and protein levels. PASMC proliferation and migration were markedly inhibited in a dosedependent manner by cyclosporin A (CsA). Furthermore, siRNA targeting NFATc2 and NFATc4 attenuated the excessive proliferation and migration and apoptosis resistance in PASMCs derived from both CON and MCT-treated rats, while NFATc3 knockdown specifically affected MCT-PASMCs. Conclusion: Our results demonstrate that CaN/NFAT signaling is activated and involved in the modulation of PASMC proliferation, migration and apoptosis in MCT-induced PAH.

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“…We did not observe effects of NFAT inhibition on expression of HNF1B. Recently, Werneck et al 26 suggested that the CNI CsA may have biological effects independent of the TGFβ-, NFAT-, NFΚB-, and PI3K/mTOR pathways. How CsA and tacrolimus can alter HNF1B mRNA expression remains to be determined but our result prompts treating HNF1B patients receiving solid organ transplant with an immunosuppressive regimen avoiding CNIs.…”

mentioning

confidence: 67%

Calcineurin Inhibitors Downregulate HNF-1β and May Affect the Outcome of HNF1B Patients After Renal Transplantation

Faguer¹,

Esposito²,

Casemayou³

et al. 2016

Transplantation

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Because HNF1B-related disease is a heterozygous condition, CNIs used to prevent rejection may induce reduced expression of the nonmutated allele of HNF1B leading to a superimposed defect of HNF-1β transcriptional activity. Taking into account the specific risk of posttransplantation diabetes mellitus and liver disorders in HNF1B patients, these findings advocate for in-depth characterization of pathways that regulate HNF1B and plead for considering individually tailored graft management that may include a CNI-free immunosuppressive regimen. Interventional studies will have to confirm this individualized approach.

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Cyclosporin A inhibits colon cancer cell growth independently of the calcineurin pathway

Cited by 34 publications

References 49 publications

The Tissue-Reconstructing Ability of Colon CSCs Is Enhanced by FK506 and Suppressed by GSK3 Inhibition

The Tissue-Reconstructing Ability of Colon CSCs Is Enhanced by FK506 and Suppressed by GSK3 Inhibition

Calcineurin/NFAT Signaling Modulates Pulmonary Artery Smooth Muscle Cell Proliferation, Migration and Apoptosis in Monocrotaline-Induced Pulmonary Arterial Hypertension Rats

Calcineurin Inhibitors Downregulate HNF-1β and May Affect the Outcome of HNF1B Patients After Renal Transplantation

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