Stabilization of E-cadherin adhesions by COX-2/GSK3β signaling is a targetable pathway in metastatic breast cancer

Balamurugan, Krishnaswamy; Poria, Dipak Kumar; Sehareen, Saadiya W; Krishnamurthy, Savitri; Tang, Wei; McKennett, Lois; Padmanaban, Veena; Czarra, Kelli; Ewald, Andrew J.; Ueno, Naoto T.; Ambs, Stefan; Sharan, Shikha; Sterneck, Esta

doi:10.1172/jci.insight.156057

Cited by 13 publications

(7 citation statements)

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“…Here, enzyme-linked immunosorbent assays (ELISAs) revealed that CXB-NPs could significantly reduce the PGE2 production in a concentration-dependent manner in all of the tested cell types, to the levels comparable to those of the parental CXB (Figure 2a-c). Furthermore, aware that the hormone-like effects of PGE2 can promote cancer cell proliferation and invasion, [27][28][29][30] we also investigated whether the PGE2-reduction by CXB-NPs can lead to inhibited proliferation of YUMM1.7 and CT26 cancer cells. As expected, and in line with our ELISA-based analyses of PGE2 levels, CXB-NPs effectively inhibited the proliferation of both cancer types to the levels similar to those of free CXB treatment (Figure 2d,e).…”

Section: Resultsmentioning

confidence: 99%

Prodrug Celecoxib‐Derived Nanoparticles Potentiate the Efficacy of Cancer Immunotherapy by Remodeling the Tumor Microenvironment

Kim,

Whang,

Kim

et al. 2024

Advanced Therapeutics

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Cyclooxygenase‐2 (COX‐2) and prostaglandin E2 (PGE2) play crucial roles in promoting tumor growth and facilitating immune evasion within the tumor microenvironment (TME) – functions that limit responses to immunotherapy. Recent research has highlighted the potential of celecoxib (CXB), a potent COX‐2 selective inhibitor, for enhancing the effectiveness of immunotherapy by blocking the COX‐2/PGE2 axis. However, the clinical application of CXB for cancer treatment is still hindered by its systemic adverse effects and lack of tumor‐targeting. Here, to address these limitations, we developed PEGylated prodrug CXB‐derived nanoparticles (CXB‐NPs), a nanomedicine designed to improve the tumor delivery of CXB while minimizing its adverse side effects. CXB‐NPs demonstrated enhanced tumor accumulation and effectively inhibited tumor growth by improving the immunosuppressive TME in immunocompetent mice, surpassing the performance of parental CXB. Furthermore, when combined with anti‐PD‐1 antibody (αPD‐1) immunotherapy, CXB‐NPs exhibited superior suppression of CT26 tumor growth compared with αPD‐1 monotherapy. This combination approach reduced the infiltration of immunosuppressive immune cells while promoting the infiltration and cytotoxicity of CD8+ T cells. Our findings indicate that CXB‐NPs capable of remodeling the TME provide a new combination therapy strategy for potentiating antitumor efficacy.This article is protected by copyright. All rights reserved

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Section: Resultsmentioning

confidence: 99%

Prodrug Celecoxib‐Derived Nanoparticles Potentiate the Efficacy of Cancer Immunotherapy by Remodeling the Tumor Microenvironment

Kim,

Whang,

Kim

et al. 2024

Advanced Therapeutics

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“…GSK3β, another type of serine/threonine protein kinase, was first described as a component of glycogen synthase regulation via its phosphorylation. As a core downstream component of PI3K/Akt [ 47 ], GSK3β mediates many biological processes in tumor cells and promotes the development and metastasis of many types of tumors through EMT [ 48 , 49 ]. One study has demonstrated that GSK3β is involved in the β-catenin/Snail1 pathway to promote the EMT process in bladder cancer [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Xiaozheng decoction for anti-bladder cancer effects via affecting the GSK3β/β-catenin signaling pathways: a network pharmacology-directed experimental investigation

Zhuang,

Mo,

Huang

et al. 2023

Chin Med

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Purpose The combination of Xiaozheng decoction with postoperative intravesical instillation has been shown to improve the prognosis of bladder cancer patients and prevent recurrence. However, the mechanisms underlying the efficacy of this herbal formula remain largely unclear. This research aims to identify the important components of Xiaozheng decoction and explore their anti-bladder cancer effect and mechanism using network pharmacology-based experiments. Methods The chemical ingredients of each herb in the Xiaozheng decoction were collected from the Traditional Chinese Medicine (TCM) database. Network pharmacology was employed to predict the target proteins and pathways of action. Disease databases were utilized to identify target genes associated with bladder cancer. A Protein–Protein Interaction (PPI) network was constructed to illustrate the interaction with intersected target proteins. Key targets were identified using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis. A compound-target-pathway network was established after molecular docking predictions. In vitro experiments with bladder cancer cell lines were conducted using core chemical components confirmed by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-qTOF-MS) to verify the conclusions of network pharmacology. Results 45 active compounds were extracted, and their relationships with Traditional Chinese Medicines (TCMs) and protein targets were presented, comprising 7 herbs, 45 active compounds, and 557 protein targets. The intersection between potential TCM target genes and bladder cancer-related genes yielded 322 genes. GO and KEGG analyses indicated that these targets may be involved in numerous cancer-related pathways. Molecular docking results showed that candidate compounds except mandenol could form stable conformations with the receptor. In vitro experiments on three bladder cancer cell lines demonstrated that quercetin and two other impressive new compounds, bisdemethoxycurcumin (BDMC) and kumatakenin, significantly promoted cancer cell apoptosis through the B-cell lymphoma 2/Bcl-2-associated X (Bcl-2/BAX) pathway and inhibited proliferation and migration through the glycogen synthase kinase 3 beta (GSK3β)/β-catenin pathway. Conclusion By employing network pharmacology and conducting in vitro experiments, the mechanism of Xiaozheng decoction’s effect against bladder cancer was tentatively elucidated, and its main active ingredients and targets were identified, providing a scientific basis for future research.

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“…For staining of intracellular FOXP3 and IFN-γ, fixation buffer (420801) and intracellular staining permeabilization wash buffer (10×; 421002; BioLegend) were used. The specific experimental procedures were the same as those used in a previous study ( 12 ). Data were acquired on a flow cytometer (CytoFLEX, Beckman Coulter, Brea, CA, USA) and analyzed using the FlowJo software (BD Biosciences).…”

Section: Methodsmentioning

confidence: 99%

“…The overexpression of IDO1 can contribute to this detrimental effect by metabolizing the essential amino acid tryptophan into tyrosine, which is an effective T-cell metabolic inhibitor that inhibits T-cell proliferation ( 11 ). One study demonstrated that the COX-2 inhibitor celecoxib could enhance the efficacy of a breast cancer vaccine ( 12 ). Recent findings have spurred us to investigate the treatment of lung cancer using a combination of gemcitabine (GEM) and celecoxib.…”

Section: Introductionmentioning

confidence: 99%

Synergistic action of gemcitabine and celecoxib in promoting the antitumor efficacy of anti-programmed death-1 monoclonal antibody by triggering immunogenic cell death

Zhu,

Zhang,

et al. 2024

Transl Cancer Res

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Background Emerging evidence suggests that immunogenic chemotherapy not only kills tumor cells but also improves the immune-suppressive tumor microenvironment by inducing immunogenic cell death (ICD), leading to sustained anti-tumor effects. The lack of ICD inducers explored in lung cancer necessitates investigation into new inducers for this context, therefore, this study aims to explore whether the gemcitabine (GEM) and celecoxib can activate the immunogenic chemotherapy progress in lung cancer tissue. Methods We assessed five chemotherapeutic agents for their ability to trigger ICD using ex vivo and in vivo experiments, including western blotting (WB), flow cytometry, and tumor preventive vaccine assays. Additionally, we evaluated the synergistic effects of GEM, celecoxib, and anti-programmed death 1 monoclonal antibody (aPD-1) in tumor-bearing mice to understand how GEM activates antitumor immunity and enhances immunochemotherapy. Results GEM was identified as an effective ICD inducer, showing high expression of calreticulin (CRT) and heat shock protein 90 (HSP90). Co-culture with GEM-treated cells [Lewis lung carcinoma (LLC) and CMT-64] enhanced dendritic cell (DC) activity, evidenced by maturation markers and increased phagocytic capacity. Moreover, celecoxib was found to enhance ICD by reducing indoleamine 2,3-dioxygenase 1 (IDO1) expression and increasing reactive oxygen species (ROS)-based endoplasmic reticulum (ER) stress. The combination therapy [GEM, celecoxib, and aPD-1 (GCP)] exhibited potent and sustained antitumor activity in immunocompetent mice, with enhanced recruitment of tumor-infiltrating lymphocytes. Conclusions These findings support the potential use of GCP therapy as a treatment option for lung cancer patients.

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Stabilization of E-cadherin adhesions by COX-2/GSK3β signaling is a targetable pathway in metastatic breast cancer

Abstract: However, AJE has unlicensed patents related to the use of K14 as a biomarker in breast cancer and to the use of antibodies as cancer treatments. AJE's spouse is an employee of Immunocore.

Cited by 13 publications

References 83 publications

Prodrug Celecoxib‐Derived Nanoparticles Potentiate the Efficacy of Cancer Immunotherapy by Remodeling the Tumor Microenvironment

Prodrug Celecoxib‐Derived Nanoparticles Potentiate the Efficacy of Cancer Immunotherapy by Remodeling the Tumor Microenvironment

Mechanisms of Xiaozheng decoction for anti-bladder cancer effects via affecting the GSK3β/β-catenin signaling pathways: a network pharmacology-directed experimental investigation

Synergistic action of gemcitabine and celecoxib in promoting the antitumor efficacy of anti-programmed death-1 monoclonal antibody by triggering immunogenic cell death

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