Celastrol attenuates the inflammatory response by inhibiting IL‑1β expression in triple‑negative breast cancer cells.
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ABSTRACT:
SUBMITTER: You D
PROVIDER: S-EPMC8042664 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Triple-negative breast cancer (TNBC) exhibits the poorest outcomes among breast cancer subtypes due to the high heterogeneity and a lasting scarcity of effectual treatments. Targeted therapies based on molecular subtypes of TNBC are critical step toward tailoring treatments to improve clinical outcomes. Gastrointestinal cancer stem cell (CSC) marker DCLK1 was reported to be highly expressed in stem cell-rich subtype of TNBC. Here, we firstly explored the impacts of DCLK1 on tumor cells as well as their immune microenvironment in TNBC and potential therapeutic strategies for TNBC patients with high DCLK1 expression. Our results disclosed that DCLK1 overexpression promoted, while knockout of DCLK1 suppressed the CSC-like traits of TNBC cells and resistance to chemotherapeutics. Besides, DCLK1 supported immune escape by inhibiting intratumoral cytotoxic T cell infiltration in TNBC and hence limited immune checkpoint inhibitors efficacy. Mechanistically, bioinformatics analysis revealed that IL-6/STAT3 signaling was significantly enriched in high DCLK1-expressing patients, and our results further revealed that DCLK1 enhanced IL-6 expression and STAT3 activation in TNBC cells, which finally gave rise to upregulated CSC traits and suppressed CD8+ T-cell activity. Inhibiting IL-6/STAT3 pathway by IL-6R antagonist, Tocilizumab or STAT3 inhibitor, S31-201 could abolish DCLK1-promoted malignant phenotypes of TNBC cells. Finally, DCLK1 was identified to be specifically and highly expressed in the mesenchymal-like subtype of TNBC and targeting DCLK1 could improve chemotherapy efficacy and activate antitumor immunity. Overall, our study revealed the potential clinical benefits of targeting DCLK1 in TNBC treatment.
| S-EPMC10108533 | biostudies-literature
Project description:Triple negative breast cancer (TNBC) has poor prognosis when compared to other breast cancer subtypes. Despite pre-clinical data supporting an immune targeted approach for TNBCs, immunotherapy has failed to demonstrate the impressive responses seen in other solid tumor malignancies. Additional strategies to modify the tumor immune microenvironment and potentiate response to immunotherapy are needed. In this review, we summarise phase III data supporting the use of immunotherapy for TNBC. We discuss the role of IL-1β in tumorigenesis and summarize pre-clinical data supporting IL-1β inhibition as a potential therapeutic strategy in TNBC. Finally, we present current trials evaluating IL-1β in breast cancer and other solid tumor malignancies and discuss future studies that may provide a strong scientific rationale for the combination of IL-1β and immunotherapy in the neoadjuvant and metastatic setting for people with TNBC.
| S-EPMC10095561 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) has the poorest prognosis among all types of breast cancer and there is yet no effective therapy. Chemotherapy is the traditional standard of care for patients with TNBC; however, treatment of TNBC with chemotherapy may lead to the enrichment of cancer stem cells (CSCs), which exhibitan enhanced capacity for self-renewal, tumor initiation and metastasis. The present study demonstrated that bufalin, a small molecular compound used in traditional Chinese medicine, exerted anticancer effects on a wide range of cancer cell lines, inhibited cell proliferation through inducing G2/M cell cycle arrest, and triggered apoptosis in the TNBC cell lines MDA-MB-231 and HCC-1937. Consistently, bufalin markedly suppressed TNBC growth in a cell line-derived xenograft model. More importantly, unlike common chemotherapeutic drugs, bufalin reduced the stemness of TNBC stem cells. A mechanistic study suggested that bufalin may suppress the proliferation of TNBC stem cells by inhibiting the expression of octamer-binding transcription factor 4 (OCT4) and sex determining region Y-box 2 (SOX2) in MDA-MB-231 and HCC-1937 cells. These results indicated that bufalin may hold promise as a therapeutic agent in TNBC, and its effects may be mediated through the SOX2/OCT4 axis.
| S-EPMC7471667 | biostudies-literature
Project description:IntroductionIn vivo, breast cancer cells spend on average 3-7 days adhered to the endothelial cells inside the vascular lumen before entering the brain. IL-1β is one of the highly upregulated molecules in brain-seeking triple negative breast cancer (TNBC) cells. In this study, the effect of IL-1β on the blood-brain barrier (BBB) and astrocytes and its role in transmigration of TNBC cells were evaluated.MethodsThe effect of IL-1β on transendothelial electrical resistance, gene and protein expression of human induced pluripotent stem cell-derived brain-specific microvascular endothelial-like cells (iBMECs) was studied. Transport of IL-1β across the iBMEC layer was investigated and the effect of IL-1β treatment of astrocytes on their cytokine and chemokine secretome was evaluated with a cytokine membrane array. Using BBB-on-a-chip devices, transmigration of MDA-MB-231 cells and their brain-seeking variant (231BR) across the iBMECs was studied, and the effect of an IL-1β neutralizing antibody on TNBC cell transmigration was investigated.ResultsWe showed that IL-1β reduces BBB integrity and induces endothelial-to-mesenchymal transition in iBMECs. IL-1β crosses the iBMEC layer and induces secretion of multiple chemokines by astrocytes, which can enhance TNBC cell transmigration across the BBB. Transmigration assays in a BBB-on-a-chip device showed that 231BR cells have a higher rate of transmigration across the iBMECs compared to MDA-MB-231 cells, and IL-1β pretreatment of BBB-on-a-chip devices increases the number of transmigrated MDA-MB-231 cells. Finally, we demonstrated that neutralizing IL-1β reduces the rate of 231BR cell transmigration.ConclusionIL-1β plays a significant role in transmigration of brain-seeking TNBC cells across the BBB.Supplementary informationThe online version contains supplementary material available at 10.1007/s12195-021-00710-y.
| S-EPMC8761198 | biostudies-literature
Project description:Gemcitabine is widely used in the treatment of breast cancer (BC). However, the resistance to drugs remains a tough concern. The study explored the potential mechanism concerning gemcitabine resistance in triple-negative BC (TNBC) in vitro. TNBC cells (TNBCC) and gemcitabine-resistance cell lines (GRC) were used. We investigated the sensitivity to gemcitabine responsive to regulation of Nod-like receptor protein 3 (NLRP3) expression in TNBCC in different gemcitabine concentrations. RT-PCR checked NLRP3 mRNA expression and MTT assessed the cell cytotoxicity. Gemcitabine resistance was studied in GRC exposed to 0, 1, 3, 5 nm gemcitabine after GRC were treated with NLRP3 agonist Nigericin sodium salt (NSS) or antagonist CY-09. Epithelial-to-mesenchymal transition (EMT) biomarkers were evaluated via RT-PCR and inflammasome IL-1β, β-catenin content and GSK-3β activity were measured by ELISA methods. Last, we inactivated the signaling and examined the NLRP3, EMT mRNA expression by RT-PCR, IL-1β, β-catenin content and GSK-3β activity by ELISA and cell cytotoxicity through MTT. NLRP3 up-regulation improved cell survival and reduced sensitivity to gemcitabine (P<0.05). NLRP3 had higher expression in GRC than TNBCC. GRC cell viability dropped as the gemcitabine concentration increased. NLRP3 up-regulation added to resistance to gemcitabine in GRC (P<0.05). NLRP3 agonist might induce EMT process, activate wnt/β-catenin signaling and IL-1β, while inactivation of wnt/β-catenin signaling could result in the inhibition of NLRP3, IL-1β and EMT as well as cell viability in GRC (P<0.05). NLRP3 could enhance resistance to gemcitabine via IL-1β/EMT/Wnt/β-catenin signaling, which suggested that NLRP3 antagonist CY-09 might be incorporated into gemcitabine treatment for TNBC.
| S-EPMC7335831 | biostudies-literature
Project description:Osteoarthritis (OA) is a degenerative joint disease associated with inflammatory response. Tripartite motif 8 (TRIM8) is a member of TRIM family that has been found to regulate inflammation. The present study was aimed to evaluate the role of TRIM8 in OA chondrocytes. Our results showed that TRIM8 expression was significantly increased in interleukin 1 beta (IL-1β)-stimulated OA chondrocytes. To knock down the TRIM8 expression in chondrocytes, the chondrocytes were transfected with si-TRIM8. Knockdown of TRIM8 attenuated IL-1β-induced production of inflammatory mediators including nitric oxide and prostaglandin E2. The increased expression levels of inducible nitric oxide synthase and cyclooxygenase-2 in IL-1β-induced chondrocytes were suppressed by TRIM8 knockdown. The IL-1β-induced production of proinflammatory cytokines including TNF-α and IL-6 was significantly decreased after transfection with si-TRIM8. Besides, knockdown of TRIM8 mitigated the IL-1β-induced decrease in aggrecan and collagen-II proteins expression and increase in matrix-degrading enzymes in chondrocytes. Furthermore, TRIM8 knockdown prevented IL-1β-induced nuclear factor kappa B (NF-κB) activation in chondrocytes. Taken together, these findings indicated that knockdown of TRIM8 attenuates IL-1β-induced inflammatory response in OA chondrocytes through the inactivation of NF-κB pathway. Thus, targeting TRIM8 might provide therapeutic treatment for OA.
| S-EPMC7563946 | biostudies-literature
Project description:Purpose:Triple-negative breast cancer (TNBC) is a refractory type of breast cancer with poor prognosis and limited choice for treatment. Previous studies had shown that TNBC has high expressions of transmembrane prostate androgen-induced protein (TMEPAI). TMEPAI was known to be induced by TGF-?/Smad signaling and have tumorigenic functions that converting TGF-? from tumor suppressor to tumor promoter and inducing epithelial-mesenchymal transition (EMT). Therefore, we aimed to define the role of TMEPAI in triple-negative breast cancer cells treatment using several anti-cancers in the presence of TGF-?. Methods:TMEPAI-knock out (KO) was carried out in a triple-negative breast cancer cell, BT549. TMEPAI editing was developed using the CRISPR-Cas9 system using two combinations of sgRNA to remove exon 4 of the TMEPAI gene entirely. Genotyping and proteomic analysis were performed to check the establishment of the TMEPAI-KO cells. Wild type (WT) and KO cells were used to determine inhibitory concentration 50% (IC50) of several anti-cancers: doxorubicin, cisplatin, paclitaxel, and bicalutamide in the presence of TGF-? treatment. Results:KO cells were successfully established by completely removing the TMEPAI gene, which was proven in genomic and proteomic analysis. Further, in TMEPAI-KO cells, we found a significant reduction of IC50 for doxorubicin and paclitaxel, and minimal effects were seen for cisplatin and bicalutamide. Our findings suggest that TGF-?-induced TMEPAI attenuates the response of TNBC to doxorubicin and paclitaxel, but not to cisplatin and bicalutamide. Conclusion:TGF-? induced TMEPAI contributes to the reduced response of TNBC treatment to doxorubicin and paclitaxel, but minimal on cisplatin and bicalutamide. Further study is needed to confirm our findings in other growth factor-induced cells, as well as in in vivo model.
| S-EPMC6986256 | biostudies-literature
Project description:Due to lack of targetable receptors and intertumoral heterogeneity, triple negative breast cancer (TNBC) remains particularly difficult to treat. Doxorubicin (DOX) is typically used as nonselective neoadjuvant chemotherapy, but the diversity of treatment efficacy remains unclear. Comparable to variability in clinical response, an experimental model of TNBC using a 4T1 syngeneic mouse model was found to elicit a differential response to a seven-day treatment regimen of DOX. Single-cell RNA sequencing identified an increase in T cells in tumors that responded to DOX treatment compared to tumors that continued to grow uninhibited. Additionally, compared to resistant tumors, DOX sensitive tumors contained significantly more CD4 T helper cells (339%), γδ T cells (727%), Naïve T cells (278%), and activated CD8 T cells (130%). Furthermore, transcriptional profiles of tumor infiltrated T cells in DOX responsive tumors revealed decreased exhaustion, increased chemokine/cytokine expression, and increased activation and cytotoxic activity. γδ T cell derived IL-17A was identified to be highly abundant in the sensitive tumor microenvironment. IL-17A was also found to directly increase sensitivity of TNBC cells in combination with DOX treatment. In TNBC tumors sensitive to DOX, increased IL-17A levels lead to a direct effect on cancer cell responsiveness and chronic stimulation of tumor infiltrated T cells leading to improved chemotherapeutic efficacy. IL-17A's role as a chemosensitive cytokine in TNBC may offer new opportunities for treating chemoresistant breast tumors and other cancer types.
| S-EPMC9340269 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) patients with upregulated Wnt/β-catenin signaling often have poor clinical prognoses. During pathological examinations of breast cancer sections stained for β-catenin, we made the serendipitous observation that relative to non-TNBC, specimens from TNBC patients have a greater abundance of nucleoli. There was a remarkable direct relationship between nuclear β-catenin and greater numbers of nucleoli in TNBC tissues. These surprising observations spurred our investigations to decipher the differential functional relevance of the nucleolus in TNBC versus non-TNBC cells. Comparative nucleolar proteomics revealed that the majority of the nucleolar proteins in TNBC cells were potential targets of β-catenin signaling. Next, we undertook an analysis of the nucleolar proteome in TNBC cells in response to β-catenin inhibition. This effort revealed that a vital component of pre-rRNA processing, LAS1 like ribosome biogenesis factor (LAS1L) was significantly decreased in the nucleoli of β-catenin inhibited TNBC cells. Here we demonstrate that LAS1L protein expression is significantly elevated in TNBC patients, and it functionally is important for mammary tumor growth in xenograft models and enables invasive attributes. Our observations highlight a novel function for β-catenin in orchestrating nucleolar activity in TNBCs.
| S-EPMC7933177 | biostudies-literature
Project description:SGLT2 inhibitor-related nephroprotection is-at least partially-mediated by anti-inflammatory drug effects, as previously demonstrated in diabetic animal and human studies, as well as hyperglycemic cell culture models. We recently presented first evidence for anti-inflammatory potential of empagliflozin (Empa) under normoglycemic conditions in human proximal tubular cells (HPTC) by demonstrating Empa-mediated inhibition of IL-1β-induced MCP-1/CCL2 and ET-1 expression on the mRNA and protein level. We now add corroborating evidence on a genome-wide level by demonstrating that Empa attenuates the expression of several inflammatory response genes in IL-1β-induced (10 ng/mL) normoglycemic HPTCs. Using microarray-hybridization analysis, 19 inflammatory response genes out of >30.000 human genes presented a consistent expression pattern, that is, inhibition of IL-1β (10 ng/mL)-stimulated gene expression by Empa (500 nM), in both HK-2 and RPTEC/TERT1 cells. Pathway enrichment analysis demonstrated statistically significant clustering of annotated pathways (enrichment score 3.64). Our transcriptomic approach reveals novel genes such as CXCL8/IL8, LOX, NOV, PTX3, and SGK1 that might be causally involved in glycemia-independent nephroprotection by SGLT2i.
| S-EPMC8151056 | biostudies-literature