IL-1β Inflammatory Cytokine-Induced TP63 Isoform ∆NP63α Signaling Cascade Contributes to Cisplatin Resistance in Human Breast Cancer Cells

Mendoza, Mónica; Ayala-Sumuano, Jorge Tonatiuh; García-Morales, Lázaro; Zamudio-Meza, Horacio; Pérez-Yépez, Eloy Andrés; Meza, Isaura

doi:10.3390/ijms20020270

Cited by 35 publications

(32 citation statements)

References 34 publications

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“…The expression of E-cadherin was significantly reduced and showed a close relationship to β-catenin nuclear localization in the tissues of CAC-untreated mice and 5-FU single therapy-treated mice. In agreement with our data, similar results on E-cadherin loss expression and translocation to the nucleus of β-catenin have been reported in breast and pancreatic cancer cells, and this is considered to be a marker of poor survival and resistance to therapies [24,49]. Therefore, these data support our proposal that STAT6 inhibition favors the response to 5-FU by regulating proteins related with cell survival, apoptosis inhibition, and acquisition of aggressive phenotypes in CAC.…”

Section: Discussionsupporting

confidence: 93%

Use of STAT6 Phosphorylation Inhibitor and Trimethylglycine as New Adjuvant Therapies for 5-Fluorouracil in Colitis-Associated Tumorigenesis

Mendoza

Sánchez-Barrera

Callejas

et al. 2020

IJMS

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Colorectal cancer (CRC) is one of the most widespread and deadly types of neoplasia around the world, where the inflammatory microenvironment has critical importance in the process of tumor growth, metastasis, and drug resistance. Despite its limited effectiveness, 5-fluorouracil (5-FU) is the main drug utilized for CRC treatment. The combination of 5-FU with other agents modestly increases its effectiveness in patients. Here, we evaluated the anti-inflammatory Trimethylglycine and the Signal transducer and activator of transcription (STAT6) inhibitor AS1517499, as possible adjuvants to 5-FU in already established cancers, using a model of colitis-associated colon cancer (CAC). We found that these adjuvant therapies induced a remarkable reduction of tumor growth when administrated together with 5-FU, correlating with a reduction in STAT6-phosphorylation. This reduction upgraded the effect of 5-FU by increasing both levels of apoptosis and markers of cell adhesion such as E-cadherin, whereas decreased epithelial–mesenchymal transition markers were associated with aggressive phenotypes and drug resistance, such as β-catenin nuclear translocation and Zinc finger protein SNAI1 (SNAI1). Additionally, Il-10, Tgf-β, and Il-17a, critical pro-tumorigenic cytokines, were downmodulated in the colon by these adjuvant therapies. In vitro assays on human colon cancer cells showed that Trimethylglycine also reduced STAT6-phosphorylation. Our study is relatively unique in focusing on the effects of the combined administration of AS1517499 and Trimethylglycine together with 5-FU on already established CAC which synergizes to markedly reduce the colon tumor load. Together, these data point to STAT6 as a valuable target for adjuvant therapy in colon cancer.

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Section: Discussionsupporting

confidence: 93%

Use of STAT6 Phosphorylation Inhibitor and Trimethylglycine as New Adjuvant Therapies for 5-Fluorouracil in Colitis-Associated Tumorigenesis

Mendoza

Sánchez-Barrera

Callejas

et al. 2020

IJMS

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“…In breast cancer, high expression of TP63 coupled with STAT6 has been shown to be associated with longer metastasis-free survival, indicating that TP63 could be involved in inhibiting the migration of breast cancer cells (Papageorgis et al, 2015). By silencing TP63 expression, breast cancer cells acquired increasing resistance to cisplatin, suggesting its role in drug reaction (Mendoza-Rodriguez et al, 2019). SORBS1 is an adaptor protein, and its overexpression inhibits the invasive capacity of tumor cells in breast cancer patients.…”

Section: Discussionmentioning

confidence: 99%

Dysregulated lncRNA-miRNA-mRNA Network Reveals Patient Survival-Associated Modules and RNA Binding Proteins in Invasive Breast Carcinoma

et al. 2020

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Breast cancer is the most common cancer in women, but few biomarkers are effective in clinic. Previous studies have shown the important roles of non-coding RNAs in diagnosis, prognosis, and therapy selection for breast cancer and have suggested the significance of integrating molecules at different levels to interpret the mechanism of breast cancer. Here, we collected transcriptome data including long non-coding RNA (lncRNA), microRNA (miRNA), and mRNA for~1,200 samples, including 1079 invasive breast carcinoma samples and 104 normal samples, from The Cancer Genome Atlas (TCGA) project. We identified differentially expressed lncRNAs, miRNAs, and mRNAs that distinguished invasive carcinoma samples from normal samples. We further constructed an integrated dysregulated network consisting of differentially expressed lncRNAs, miRNAs, and mRNAs and found housekeeping and cancer-related functions. Moreover, 58 RNA binding proteins (RBPs) involved in biological processes that are essential to maintain cell survival were found in the dysregulated network, and 10 were correlated with overall survival. In addition, we identified two modules that stratify patients into high-and low-risk subgroups. The expression patterns of these two modules were significantly different in invasive carcinoma versus normal samples, and some molecules were high-confidence biomarkers of breast cancer. Together, these data demonstrated an important clinical application for improving outcome prediction for invasive breast cancers.

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“…However, anandamide-induced degradation of cytoplasmic β-catenin, while CBD relocated β-catenin at the adherens junctions. In both cases the expression of malignant markers in 6D cells was greatly reduced [5,16,17]. In this work, we analyzed the expression of two genes, BIRC3 and TP63, the expression of which was increased by the activation of the IL-1β/IL-1R/β-catenin pathway.…”

Section: Discussionmentioning

confidence: 99%

“…As the above data revealed that addition of CBD to 6D cells caused morphological and molecular changes described in the IL-1β-induced EMT, we investigated if CBD could have a negative effect on the expression of genes and proteins that participate in this process [16,17]. Therefore, qRT-PCR analysis was performed for BIRC3, TP63, and ID1 genes.…”

Section: Cbd Decreased the Expression Of Proteins Related To The Il-1mentioning

confidence: 99%

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CBD Reverts the Mesenchymal Invasive Phenotype of Breast Cancer Cells Induced by the Inflammatory Cytokine IL-1β

García-Morales

Castillo

Tapia-Ramı́rez

et al. 2020

IJMS

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Cannabidiol (CBD) has been used to treat a variety of cancers and inflammatory conditions with controversial results. In previous work, we have shown that breast cancer MCF-7 cells, selected by their response to inflammatory IL-1β cytokine, acquire a malignant phenotype (6D cells) through an epithelial–mesenchymal transition (EMT). We evaluated CBD as a potential inhibitor of this transition and inducer of reversion to a non-invasive phenotype. It decreased 6D cell viability, downregulating expression of receptor CB1. The CBD blocked migration and progression of the IL-1β-induced signaling pathway IL-1β/IL-1RI/β-catenin, the driver of EMT. Cannabidiol reestablished the epithelial organization lost by dispersion of the cells and re-localized E-cadherin and β-catenin at the adherens junctions. It also prevented β-catenin nuclear translocation and decreased over-expression of genes for ∆Np63α, BIRC3, and ID1 proteins, induced by IL-1β for acquisition of malignant features. Cannabidiol inhibited the protein kinase B (AKT) activation, a crucial effector in the IL-1β/IL-1RI/β-catenin pathway, indicating that at this point there is crosstalk between IL-1β and CBD signaling which results in phenotype reversion. Our 6D cell system allowed step-by-step analysis of the phenotype transition and better understanding of mechanisms by which CBD blocks and reverts the effects of inflammatory IL-1β in the EMT.

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IL-1β Inflammatory Cytokine-Induced TP63 Isoform ∆NP63α Signaling Cascade Contributes to Cisplatin Resistance in Human Breast Cancer Cells

Cited by 35 publications

References 34 publications

Use of STAT6 Phosphorylation Inhibitor and Trimethylglycine as New Adjuvant Therapies for 5-Fluorouracil in Colitis-Associated Tumorigenesis

Use of STAT6 Phosphorylation Inhibitor and Trimethylglycine as New Adjuvant Therapies for 5-Fluorouracil in Colitis-Associated Tumorigenesis

Dysregulated lncRNA-miRNA-mRNA Network Reveals Patient Survival-Associated Modules and RNA Binding Proteins in Invasive Breast Carcinoma

CBD Reverts the Mesenchymal Invasive Phenotype of Breast Cancer Cells Induced by the Inflammatory Cytokine IL-1β

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