Ruxolitinib induces apoptosis of human colorectal cancer cells by downregulating the JAK1/2‑STAT1‑Mcl‑1 axis

Li, Xia; Wang, Zhe; Zhang, Shengjie; Yao, Qinghua; Chen, Wei; Liu, Feiyan

doi:10.3892/ol.2021.12613

Cited by 11 publications

(8 citation statements)

References 54 publications

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“…For WGD in COAD, bosutinib and ruxolitinib were suggested to target PLK1 kinase, a pivotal regulator of mitotic events frequently overexpressed in colon cancers 55–58 . These drugs have been reported to induce apoptosis in colon cancer cells 59,60 . Sunitinib was recommended as the most suitable drug for BRCA patients with WGD, supported by its efficacy in BRCA reported in some studies 61,62 , although caution is advised when applying it to metastatic breast cancer patients 63 .…”

Section: Resultsmentioning

confidence: 99%

Pan-cancer proteogenomic landscape of whole-genome doubling reveals putative therapeutic targets in various cancer types

Chang,

Hwang,

Song

et al. 2024

Preprint

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Background: Whole-genome doubling (WGD) is prevalent in cancer and drives tumor development and chromosomal instability. Driver mutations in mitotic cell cycle genes and cell cycle upregulation have been reported as the major molecular underpinnings of WGD tumors. However, the underlying genomic signatures and regulatory networks involved in gene transcription and kinase phosphorylation remain unclear. Here, we aimed to comprehensively decipher the molecular landscape underlying WGD tumors. Methods: We performed a pan-cancer proteogenomic analysis and compared 10 cancer types by integrating genomic, transcriptomic, proteomic, and phosphoproteomic datasets from the Clinical Proteomic Tumor Analysis Consortium (CPTAC). We also integrated the cancer dependency data of each cancer cell line and the survival properties of each cancer patient to propose promising therapeutic targets for patients with WGD. Results: Our study delineated distinct copy number signatures characterizing WGD-positive tumors into three major groups: highly unstable genome, focal instability, and tetraploidy. Furthermore, the analysis revealed the heterogeneous mechanisms underlying WGD across cancer types with specific structural variation patterns. Upregulation of the cell cycle and downregulation of the immune response were found to be specific to certain WGD tumor types. Transcription factors (TFs) and kinases exhibit cancer-specific activities, emphasizing the need for tailored therapeutic approaches. Conclusion: This study introduces an integrative approach to identify potential TF targets for drug development, highlighting BPTF as a promising candidate for the treatment of head and neck squamous cell carcinoma. Additionally, drug repurposing strategies have been proposed, suggesting potential drugs for the treatment of WGD-associated cancers. Our findings offer insights into the heterogeneity of WGD and have implications for precision medicine approaches for cancer treatment.

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Section: Resultsmentioning

confidence: 99%

Pan-cancer proteogenomic landscape of whole-genome doubling reveals putative therapeutic targets in various cancer types

Chang,

Hwang,

Song

et al. 2024

Preprint

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“…Some studies have shown that immune checkpoints such as PD-1, CTLA-4 and LAG-3 are upregulated on the surface of T cells in breast tumor tissues. The epigenetic modifications behind their upregulation are depends on the methylation of DNA and the distribution of inhibitory histone [28]. Therefore, the combination of targeted drugs and STAT1 blocking function is a new strategy for the treatment of tumors.…”

Section: Discussionmentioning

confidence: 99%

Expression Patterns of Immune Checkpoints in Breast Cancer Patients

Ma,

Yan

et al. 2023

AJST

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Background: immunotherapy with immune checkpoint inhibitors (ICIs) for solid tumors had significantly improved overall survival (OS). Positive response to PD-1/PD-L1 blockades was observed in the treatment of solid tumors. Breast cancer (BC) patients are no exception. However, the efficacy of immunocheckpoint therapy in BC patients remains poor. A particularly important factor is the lack of studies on the expression patterns of immune checkpoints in BC patients. Methods：This article summarizes the expression of immune checkpoints such as PD-1, PD-L1, STAT1, CTLA-4 in BC, and analyzes the relationship between the expression of these immune checkpoints and OS.Results: It was found that increased expression of PD-1, PD-L1, STAT1, CTLA-4 was associated with poor OS in BC patients. In addition, co-expression of PD-L1 with PD-1, STAT1or CTLA-4 and co-expression of PD-1 with CTLA-4was related to poor OS. We analyzed associations between the proportionate expression of PD-L1 and PD-1, PD-L1 and STAT1, PD-1 and CTLA-4, PD-1 and LAG3, PD-L1 and CTLA-4 in BC patients, there was significance in correlation in both of the BC patients. Conclusions: our results suggest that transcriptome-based co-expression of STAT1 and PD-L1 is a predictor for poor OS in BC patients, which might provide novel insight into designing combinational targeted therapy for BC.

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“…In rheumatoid arthritis, continuous activation of JAK signaling in synovial joints results in the most pronounced “apoptosis resistance” in apoptotic chondrocytes ( Malemud, 2018 ). Tofacitinib or ruxolitinib, JAK small molecule inhibitor, downregulated myeloid cell leukemia-1 mRNA level and decreased its protein level, which enabled BAK to trigger necroptosis ( Thapa et al, 2013 ; Li et al, 2021 ). Therefore, we speculate that the JAK1 is associated with the negative regulation of necroptosis in ICM.…”

Section: Discussionmentioning

confidence: 99%

A risk model developed based on necroptosis to assess progression for ischemic cardiomyopathy and identify possible therapeutic drugs

Wang

Zhu

et al. 2022

Front. Pharmacol.

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Object: Ischemic cardiomyopathy (ICM), with high morbidity and mortality, is the most common cause of heart failure. Cardiovascular remodeling secondary to chronic myocardial ischemia is the main cause of its progression. A recently identified type of programmed cell death called necroptosis is crucial in the development of various cardiovascular diseases. However, the function role of necroptosis in cardiac remodeling of ICM has not been elucidated. Our study aimed to screen for genes associated with necroptosis and construct a risk score to assess the progression and evaluate the prognosis of ICM patients, and further to search for potentially therapeutic drugs.Methods: The gene expression profiling was obtained from the GEO database. LASSO regression analysis was used to construct necroptosis-related gene signatures associated with ICM progression and prognosis. TF-gene and miRNA-gene networks were constructed to identify the regulatory targets of potential necroptosis-related signature genes. Pathway alterations in patients with high necroptosis-related score (NRS) were analyzed by GO, KEGG, GSEA analysis, and immune cell infiltration was estimated by ImmuCellAI analysis. CMap analysis was performed to screen potential small molecule compounds targeting patients with high NRS. Independent risk analyses were performed using nomograms.Results: Six necroptosis-related signature genes (STAT4, TNFSF10, CHMP5, CHMP18, JAK1, and CFLAR) were used to define the NRS, with areas under the ROC curves of 0.833, 0.765, and 0.75 for training test, test set, and validation set, respectively. Transcription factors FOXC1 and hsa-miR-124-3p miRNA may be regulators of signature genes. Patients with higher NRS have pathway enriched in fibrosis and metabolism and elevated nTreg cells. AZD-7762 may be an effective drug to improve the prognosis of patients with high NRS. A feature-based nomogram was constructed from which patients could derive clinical benefit.Conclusion: Our results reveal 6 necroptosis gene signatures that can evaluate the progression and prognosis of ICM with high clinical value, and identify potential targets that could help improve cardiovascular remodeling.

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Ruxolitinib induces apoptosis of human colorectal cancer cells by downregulating the JAK1/2‑STAT1‑Mcl‑1 axis

Cited by 11 publications

References 54 publications

Pan-cancer proteogenomic landscape of whole-genome doubling reveals putative therapeutic targets in various cancer types

Pan-cancer proteogenomic landscape of whole-genome doubling reveals putative therapeutic targets in various cancer types

Expression Patterns of Immune Checkpoints in Breast Cancer Patients

A risk model developed based on necroptosis to assess progression for ischemic cardiomyopathy and identify possible therapeutic drugs

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