Digitoxin induces apoptosis in cancer cells by inhibiting nuclear factor of activated T-cells-driven c-MYC expression

Yang, Qing; Dalgard, Clifton L.; Eidelman, Ofer; Jozwik, Catherine; Pollard, Bette S.; Srivastava, Meera; Pollard, Harvey B.

doi:10.4103/1477-3163.112268

Cited by 17 publications

(9 citation statements)

References 47 publications

(57 reference statements)

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“…Up to date, most of the NFAT inhibitors have been developed to nonspecifically inhibit all calcineurin-responsive NFAT isoforms no matter whether they exert their roles as an oncogene or a tumor suppressor, resulting in suboptimal efficacy against human cancer and unexpected side effects on human immune system. Several NFAT inhibitors that target either oncogenic NFAT isoforms, such as helenalin [ 51 ] and zoledronic acid [ 52 ], or NFAT-DNA binding, such as imperatorin [ 53 ] and digitoxin [ 54 ] have shown significant anticancer activities in vitro and in vivo . The present study reports, for the first time, a novel NFAT1 inhibitor JapA that targets both oncogenic NFAT1 and NFAT1 interaction with the MDM2 P2 promoter.…”

Section: Discussionmentioning

confidence: 99%

Inhibiting NFAT1 for breast cancer therapy: New insights into the mechanism of action of MDM2 inhibitor JapA

et al. 2015

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Transcription factor NFAT1 has been recently identified as a new regulator of the MDM2 oncogene. Targeting the NFAT1-MDM2 pathway represents a novel approach to cancer therapy. We have recently identified a natural product MDM2 inhibitor, termed JapA. As a specific and potent MDM2 inhibitor, JapA inhibits MDM2 at transcriptional and post-translational levels. However, the molecular mechanism remains to be fully elucidated for its inhibitory effects on MDM2 transcription. Herein, we reported that JapA inhibited NFAT1 and NFAT1-mediated MDM2 transcription, which contributed to the anticancer activity of JapA. Its effects on the expression and activity of NFAT1 were examined in various breast cancer cell lines in vitro and in MCF-7 and MDA-MB-231 xenograft tumors in vivo. The specificity of JapA in targeting NFAT1 and NFAT1-MDM2 pathway and the importance of NFAT1 inhibition in JapA's anticancer activity were demonstrated using NFAT1 overexpression and knockdown cell lines and the pharmacological activators and inhibitors of NFAT1 signaling. Our results indicated that JapA inhibited NFAT1 signaling in breast cancer cells in vitro and in vivo, which plays a pivotal role in its anticancer activity. JapA inhibited the nuclear localization of NFAT1, disrupted the NFAT1-MDM2 P2 promoter complex, and induced NFAT1 proteasomal degradation, resulting in the repression of MDM2 transcription. In conclusion, JapA is a novel NFAT1 inhibitor and the NFAT1 inhibition is responsible for the JapA-induced repression of MDM2 transcription, contributing to its anticancer activity. The results may pave an avenue for validating the NFAT1-MDM2 pathway as a novel molecular target for cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Inhibiting NFAT1 for breast cancer therapy: New insights into the mechanism of action of MDM2 inhibitor JapA

et al. 2015

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“…Certain inhibitors such as UR-1505 and digitoxin block the binding of NFAT to DNA ( 155 ). Remarkably, digitoxin specifically inhibits interaction between NFAT1 and the c- Myc promoter and thereby inhibits c-Myc-dependent transcription ( 162 ). The FOXP3-derived peptide, FOXP3 393–403, specifically inhibits FOXP3/NFAT interaction.…”

Section: Nfat Targeting Drugs For Autoimmunity: Beyond Cyclosporine Amentioning

confidence: 99%

Revisiting the Concept of Targeting NFAT to Control T Cell Immunity and Autoimmune Diseases

2018

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The nuclear factor of activated T cells (NFAT) family of transcription factors, which includes NFAT1, NFAT2, and NFAT4, are well-known to play important roles in T cell activation. Most of NFAT proteins are controlled by calcium influx upon T cell receptor and costimulatory signaling results increase of IL-2 and IL-2 receptor. NFAT3 however is not shown to be expressed in T cells and NFAT5 has not much highlighted in T cell functions yet. Recent studies demonstrate that the NFAT family proteins involve in function of lineage-specific transcription factors during differentiation of T helper 1 (Th1), Th2, Th17, regulatory T (Treg), and follicular helper T cells (Tfh). They have been studied to make physical interaction with the other transcription factors like GATA3 or Foxp3 and they also regulate Th cell signature gene expressions by direct binding on promotor region of target genes. From last decades, NFAT functions in T cells have been targeted to develop immune modulatory drugs for controlling T cell immunity in autoimmune diseases like cyclosporine A, FK506, etc. Due to their undesirable side defects, only limited application is available in human diseases. This review focuses on the recent advances in development of NFAT targeting drug as well as our understanding of each NFAT family protein in T cell biology. We also discuss updated detail molecular mechanism of NFAT functions in T cells, which would lead us to suggest an idea for developing specific NFAT inhibitors as a therapeutic drug for autoimmune diseases.

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“…Previously, a number of studies have focused on the anticancer potential of digitoxin and verified notable antitumor activities of digitoxin in lung cancer ( 17 ), pancreatic cancer ( 18 ), glioma ( 19 ), liver cancer ( 20 ), prostate cancer ( 21 ) and melanoma ( 22 ). Mechanistic studies have revealed that the growth inhibitory effect of digitoxin was associated with the induction of apoptosis ( 23 ), inhibition of epithelial-mesenchymal transition ( 21 ) and suppression of cancer cell stemness ( 24 ); however, the underlying mechanism of action of digitoxin against multidrug-resistant HCC cells has not been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Digitoxin inhibits proliferation of multidrug‑resistant HepG2 cells through G2/M cell cycle arrest and apoptosis

et al. 2020

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Hepatocellular carcinoma (HCC) remains a challenge in the medical field due to its high malignancy and mortality rates particularly for HCC, which has developed multidrug resistance. Therefore, the identification of efficient chemotherapeutic drugs for multidrug resistant HCC has become an urgent issue. Natural products have always been of significance in drug discovery. In the present study, a cell-based method was used to screen a natural compound library, which consisted of 78 compounds, and the doxorubicin-resistant cancer cell line, HepG2/ADM, as screening tools. The findings of the present study led to the shortlisting of one of the compounds, digitoxin, which displayed an inhibitory effect on HepG2/ADM cells, with 50% inhibitory concentration values of 132.65±3.83, 52.29±6.26, and 9.13±3.67 nM for 24, 48, and 72 h, respectively. Immunofluorescence, western blotting and cell cycle analyses revealed that digitoxin induced G 2 /M cell cycle arrest via the serine/threonine-protein kinase ATR (ATR)-serine/threonine-protein kinase Chk2 (CHK2)-M-phase inducer phosphatase 3 (CDC25C) signaling pathway in HepG2/ADM cells, which may have resulted from a DNA double-stranded break. Digitoxin also induced mitochondrial apoptosis, which was characterized by changes in the interaction between Bcl-2 and Bax, the release of cytochrome c , as well as the activation of the caspase-3 and −9. To the best of our knowledge, the present study is the first report that digitoxin displays an anti-HCC effect on HepG2/ADM cells through G 2 /M cell cycle arrest, which was mediated by the ATR-CHK2-CDC25C signaling pathway and mitochondrial apoptosis. Therefore, digitoxin could be a promising chemotherapeutic agent for the treatment of patients with HCC.

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Digitoxin induces apoptosis in cancer cells by inhibiting nuclear factor of activated T-cells-driven c-MYC expression

Cited by 17 publications

References 47 publications

Inhibiting NFAT1 for breast cancer therapy: New insights into the mechanism of action of MDM2 inhibitor JapA

Inhibiting NFAT1 for breast cancer therapy: New insights into the mechanism of action of MDM2 inhibitor JapA

Revisiting the Concept of Targeting NFAT to Control T Cell Immunity and Autoimmune Diseases

Digitoxin inhibits proliferation of multidrug‑resistant HepG2 cells through G2/M cell cycle arrest and apoptosis

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