Targeting STAT3 in cancer and autoimmune diseases

Gharibi, Tohid; Babaloo, Zohreh; Hosseini, Abdolkarim; Abdollahpour‐Alitappeh, Meghdad; Hashemi, Vida; Marofi, Faroogh; Nejati, Kazem; Baradaran, Behzad

doi:10.1016/j.ejphar.2020.173107

Cited by 86 publications

(52 citation statements)

References 320 publications

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“…An extensive body of evidence links STAT3 with autoimmune diseases. Most of the evidence is related to the capacity of STAT3 to influence the differentiation of lymphoid cells, such as Th17 and Treg CD4 T cells [47]. Indeed, gain-of-function mutations have been reported in patients with autoimmune conditions [48,49].…”

Section: Discussionmentioning

confidence: 99%

Prolactin Rescues Immature B Cells from Apoptosis-Induced BCR-Aggregation through STAT3, Bcl2a1a, Bcl2l2, and Birc5 in Lupus-Prone MRL/lpr Mice

Flores-Fernández

Aponte-López

Suárez-Arriaga

et al. 2021

Cells

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Self-reactive immature B cells are eliminated through apoptosis by tolerance mechanisms, failing to eliminate these cells results in autoimmune diseases. Prolactin is known to rescue immature B cells from B cell receptor engagement-induced apoptosis in lupus-prone mice. The objective of this study was to characterize in vitro prolactin signaling in immature B cells, using sorting, PCR array, RT-PCR, flow cytometry, and chromatin immunoprecipitation. We found that all B cell maturation stages in bone marrow express the prolactin receptor long isoform, in both wild-type and MRL/lpr mice, but its expression increased only in the immature B cells of the latter, particularly at the onset of lupus. In these cells, activation of the prolactin receptor promoted STAT3 phosphorylation and upregulation of the antiapoptotic Bcl2a1a, Bcl2l2, and Birc5 genes. STAT3 binding to the promoter region of these genes was confirmed through chromatin immunoprecipitation. Furthermore, inhibitors of prolactin signaling and STAT3 activation abolished the prolactin rescue of self-engaged MRL/lpr immature B cells. These results support a mechanism in which prolactin participates in the emergence of lupus through the rescue of self-reactive immature B cell clones from central tolerance clonal deletion through the activation of STAT3 and transcriptional regulation of a complex network of genes related to apoptosis resistance.

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Section: Discussionmentioning

confidence: 99%

Prolactin Rescues Immature B Cells from Apoptosis-Induced BCR-Aggregation through STAT3, Bcl2a1a, Bcl2l2, and Birc5 in Lupus-Prone MRL/lpr Mice

Flores-Fernández

Aponte-López

Suárez-Arriaga

et al. 2021

Cells

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“…The activity of STAT3 is regulated by diverse mechanisms, including an array of post-translational modifications, such as phosphorylation (e.g., Tyr705 and Ser727) (33). Since STAT3 serves vital roles in the progression of most human cancer types, it has been suggested that STAT3 could be an important candidate therapeutic target for tumor treatment (34). It has also been reported that different mechanisms are involved in STAT3 inhibition, including suppression of tyrosine enzymes that contribute to the phosphorylation or activation of STAT3, inhibition of STAT3-mediated transcription, repression of nuclear localization of STAT3 and inhibition of the interaction between STAT3 and its target gene (35).…”

Section: Discussionmentioning

confidence: 99%

Chidamide induces apoptosis in DLBCL cells by suppressing the HDACs/STAT3/Bcl‑2 pathway

et al. 2021

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Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous malignant tumor type, and epigenetic modifications such as acetylation or deacetylation serve vital roles in its development. Chidamide, a novel histone deacetylase inhibitor, exerts an anticancer effect against various types of cancer. The present study aimed to evaluate the cellular effect of chidamide on a number of DLBCL cell lines and to investigate its underlying mechanism. The results demonstrated that chidamide induced the death of these cells in a concentration-(0-30 µmol/l) and time-dependent (24-72 h) manner, as determined using the Cell Counting Kit-8 cell viability assay. Moreover, chidamide promoted cellular apoptosis, which was identified via flow cytometry and western blot analysis, with an increase in cleaved caspase-3 expression and a decrease in Bcl-2 expression. Chidamide treatment also decreased the expression level of STAT3 and its phosphorylation, which was accompanied by the downregulation of a class-I histone deacetylase (HDAC) inhibitor, chidamide. Collectively, these data suggested that chidamide can be a potent therapeutic agent to treat DLBCL by inducing the apoptotic death of DLBCL cells by inhibiting the HDACs/STAT3/Bcl-2 pathway.

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“…SPR assay indicated that EGCG significantly interrupted STAT3 peptide binding at micromolar concentrations, and docking experiments indicated that EGCG competitively binds to the STAT3 SH2 domain, inhibiting STAT3 phosphorylation and signaling [ 63 ]. Importantly, in the immune system, most of the cytokine receptors, including the receptors of IL-6, IL-10, IL-21, and IL-23, can activate STAT3 indicating that it is an important nuclear factor for the regulation of immune responses and autoimmunity [ 64 ]. It is also known that in COVID-19 hyper-inflammatory condition, high level of IL-6 seem to be the main prognostic factor for worse outcomes.…”

Section: Egcg Molecular Mechanisms That Could Counteract Covid-19 mentioning

confidence: 99%

Protective Effect of Epigallocatechin-3-Gallate (EGCG) in Diseases with Uncontrolled Immune Activation: Could Such a Scenario Be Helpful to Counteract COVID-19?

Menegazzi

Campagnari

Bertoldi

et al. 2020

IJMS

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Some coronavirus disease 2019 (COVID-19) patients develop acute pneumonia which can result in a cytokine storm syndrome in response to Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infection. The most effective anti-inflammatory drugs employed so far in severe COVID-19 belong to the cytokine-directed biological agents, widely used in the management of many autoimmune diseases. In this paper we analyze the efficacy of epigallocatechin 3-gallate (EGCG), the most abundant ingredient in green tea leaves and a well-known antioxidant, in counteracting autoimmune diseases, which are dominated by a massive cytokines production. Indeed, many studies registered that EGCG inhibits signal transducer and activator of transcription (STAT)1/3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription factors, whose activities are crucial in a multiplicity of downstream pro-inflammatory signaling pathways. Importantly, the safety of EGCG/green tea extract supplementation is well documented in many clinical trials, as discussed in this review. Since EGCG can restore the natural immunological homeostasis in many different autoimmune diseases, we propose here a supplementation therapy with EGCG in COVID-19 patients. Besides some antiviral and anti-sepsis actions, the major EGCG benefits lie in its anti-fibrotic effect and in the ability to simultaneously downregulate expression and signaling of many inflammatory mediators. In conclusion, EGCG can be considered a potential safe natural supplement to counteract hyper-inflammation growing in COVID-19.

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Targeting STAT3 in cancer and autoimmune diseases

Cited by 86 publications

References 320 publications

Prolactin Rescues Immature B Cells from Apoptosis-Induced BCR-Aggregation through STAT3, Bcl2a1a, Bcl2l2, and Birc5 in Lupus-Prone MRL/lpr Mice

Prolactin Rescues Immature B Cells from Apoptosis-Induced BCR-Aggregation through STAT3, Bcl2a1a, Bcl2l2, and Birc5 in Lupus-Prone MRL/lpr Mice

Chidamide induces apoptosis in DLBCL cells by suppressing the HDACs/STAT3/Bcl‑2 pathway

Protective Effect of Epigallocatechin-3-Gallate (EGCG) in Diseases with Uncontrolled Immune Activation: Could Such a Scenario Be Helpful to Counteract COVID-19?

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