NFATC4 promotes quiescence and chemotherapy resistance in ovarian cancer

Cole, Alexander J.; Iyengar, M. R. S.; Panesso-Gómez, Santiago; O’Hayer, Patrick; Chan, Daniel; Delgoffe, Greg M.; Aird, Katherine M.; Yoon, Euisik; Bai, Shoumei; Buckanovich, Ronald J.

doi:10.1172/jci.insight.131486

Cited by 35 publications

(25 citation statements)

References 57 publications

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“…The NFAT proteins were widely concerned in the immune system, while recent studies indicated that they are functionally active in several nonimmune cells and participate in tumor progression (Baksh et al, 2002;Graef et al, 2003;Neal and Clipstone, 2003). Our study discovered that high expression of NFATC4 was associated with poor prognosis of AML, which was consistent with reports in pancreatic cancer and ovarian cancer (Hessmann et al, 2016;Cole et al, 2020). In these tumors, NFATC4 participates in cancer progression through promoting tumor cell proliferation or chemotherapy resistance, while we inferred that it regulates immune responses in the progression of AML.…”

Section: Discussionsupporting

confidence: 91%

Increased NFATC4 Correlates With Poor Prognosis of AML Through Recruiting Regulatory T Cells

et al. 2020

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Despite that immune responses play important roles in acute myeloid leukemia (AML), immunotherapy is still not widely used in AML due to lack of an ideal target. Therefore, we identified key immune genes and cellular components in AML by an integrated bioinformatics analysis, trying to find potential targets for AML. Eighty-six differentially expressed immune genes (DEIGs) were identified from 751 differentially expressed genes (DEGs) between AML patients with fair prognosis and poor prognosis from the TCGA database. Among them, nine prognostic immune genes, including NCR2, NPDC1, KIR2DL4, KLC3, TWIST1, SNORD3B-1, NFATC4, XCR1, and LEFTY1, were identified by univariate Cox regression analysis. A multivariable prediction model was established based on prognostic immune genes. Kaplan–Meier survival curve analysis indicated that patients in the high-risk group had a shorter survival rate and higher mortality than those in the low-risk group (P < 0.001), indicating good effectiveness of the model. Furthermore, nuclear factors of activated T cells-4 (NFATC4) was recognized as the key immune gene identified by co-expression of differentially expressed transcription factors (DETFs) and prognostic immune genes. ATP-binding cassette transporters (ABC transporters) were the downstream KEGG pathway of NFATC4, identified by gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA). To explore the immune responses NFATC4 was involved in, an immune gene set of T cell co-stimulation was identified by single-cell GSEA (ssGSEA) and Pearson correlation analysis, positively associated with NFATC4 in AML (R = 0.323, P < 0.001, positive). In order to find out the immune cell types affected by NFATC4, the CIBERSORT algorithm and Pearson correlation analysis were applied, and it was revealed that regulatory T cells (Tregs) have the highest correlation with NFATC4 (R = 0.526, P < 0.001, positive) in AML from 22 subsets of tumor-infiltrating immune cells. The results of this study were supported by multi-omics database validation. In all, our study indicated that NFATC4 was the key immune gene in AML poor prognosis through recruiting Tregs, suggesting that NFATC4 might serve as a new therapy target for AML.

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Section: Discussionsupporting

confidence: 91%

Increased NFATC4 Correlates With Poor Prognosis of AML Through Recruiting Regulatory T Cells

et al. 2020

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“…4 ) ( 74 , 84 , 85 ). There are already several surface markers for ovarian CSC identification, including MyoD, CD44, CD117 ( 86 ), CD133 ( 87 ), ALDH ( 76 ) and nuclear factor of activated T cells, cytoplasmic 4 (NFATC4) ( 88 , 89 ).…”

Section: Molecular Mechanisms Of Platinum-based Chemotherapy Resistan...mentioning

confidence: 99%

“…Accordingly, the PI3K inhibitor BEZ235 renders EOC cells sensitive to cisplatin by inhibiting the expression of EMT and CSC markers ( 91 ). NFATC4 is enriched in ovarian CSC-like cells, which leads to chemotherapy resistance by downregulating MYC at an early stage, helping cells enter a quiescent state ( 88 ). The aforementioned studies revealed that NFATC4 is a significant therapeutic target for ovarian cancer that is worthy of in-depth study.…”

Section: Molecular Mechanisms Of Platinum-based Chemotherapy Resistan...mentioning

confidence: 99%

Molecular mechanisms of platinum‑based chemotherapy resistance in ovarian cancer (Review)

et al. 2022

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Cisplatin is one of the most effective chemotherapy drugs for ovarian cancer, but resistance is common. The initial response to platinum-based chemotherapy is as high as 80%, but in most advanced patients, final relapse and death are caused by acquired drug resistance. The development of resistance to therapy in ovarian cancer is a significant hindrance to therapeutic efficacy. The resistance of ovarian cancer cells to chemotherapeutic mechanisms is rather complex and includes multidrug resistance, DNA damage repair, cell metabolism, oxidative stress, cell cycle regulation, cancer stem cells, immunity, apoptotic pathways, autophagy and abnormal signaling pathways. The present review provided an update of recent developments in our understanding of the mechanisms of ovarian cancer platinum-based chemotherapy resistance, discussed current and emerging approaches for targeting these patients and presented challenges associated with these approaches, with a focus on development and overcoming resistance. Contents1. Introduction 2. Literature review methods 3. Molecular mechanisms of platinum-based chemotherapy resistance in ovarian cancer 4. Conclusions

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“…Studies have shown a direct correlation between CSC abundance and the onset of relapse, suggesting CSCs promote chemotherapy resistance [24][25][26] . For example, expression of different biomarkers for CSCs, CD44, ALDH, CD133 and MyD88, was observed to be associated with chemotherapy resistance and poor patient outcome in EOC [27][28][29] . Recently, the transcription factor NFATC4 (nuclear factor of activated T cells cytoplasmic 4) was identified as a regulator of quiescence in ovarian cancer, enriched in ovarian CSCs and associated with chemotherapy resistance and poor prognosis [30] .…”

Section: Introductionmentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR pathway in epithelial ovarian cancer, therapeutic treatment options for platinum-resistant ovarian cancer

Rinne¹,

Christie²,

Ardasheva³

et al. 2021

CDR

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The survival rates for women with ovarian cancer have shown scant improvement in recent years, with a 5-year survival rate of less than 40% for women diagnosed with advanced ovarian cancer. High-grade serous ovarian cancer (HGSOC) is the most lethal subtype where the majority of women develop recurrent disease and chemotherapy resistance, despite over 70%-80% of patients initially responding to platinum-based chemotherapy. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway regulates many vital processes such as cell growth, survival and metabolism. However, this pathway is frequently dysregulated in cancers including different subtypes of ovarian cancer, through amplification or somatic mutations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), amplification of AKT isoforms, or deletion or inactivation of PTEN. Further evidence indicates a role for the PI3K/AKT/mTOR pathway in the development of chemotherapy resistance in ovarian cancer. Thus, targeting key nodes of the PI3K/AKT/mTOR pathway is a potential therapeutic prospect. In this review, we outline dysregulation of PI3K signaling in ovarian cancer, with a particular emphasis on HGSOC and platinum-resistant disease. We review preclinical evidence for inhibitors of the main components of the PI3K pathway and highlight past, current and upcoming trials in ovarian cancers for different inhibitors of the pathway. Whilst no inhibitors of the PI3K/AKT/mTOR pathway have thus far advanced to the clinic for the treatment of ovarian cancer, several

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NFATC4 promotes quiescence and chemotherapy resistance in ovarian cancer

Cited by 35 publications

References 57 publications

Increased NFATC4 Correlates With Poor Prognosis of AML Through Recruiting Regulatory T Cells

Increased NFATC4 Correlates With Poor Prognosis of AML Through Recruiting Regulatory T Cells

Molecular mechanisms of platinum‑based chemotherapy resistance in ovarian cancer (Review)

Targeting the PI3K/AKT/mTOR pathway in epithelial ovarian cancer, therapeutic treatment options for platinum-resistant ovarian cancer

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