{"title":"PPA1, TRIM68 and FBXO46: Potential Therapeutic Targets for Triple Negative Breast Cancer.","authors":"Fatima Haider, Nida Syed, Syeda Abiha Zehra Jaffari, Basir Syed, Aftab Ahmed, Shamshad Zarina, Zehra Hashim","doi":"10.2174/0113892037334325241014053319","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer with a high recurrence rate. A new therapeutic intervention is urgently needed to combat this lethal subtype. The identification of biomarkers is also crucial for improving outcomes in TNBC.</p><p><strong>Method: </strong>The cell cytotoxicity of ML364 (2-(4-Methylphenylsulfonamido)-N-(4-phenylthiazol- 2-yl)-4-(trifluoromethyl)benzamide) was measured at different concentrations of ML364 in TNBC-treated and untreated cells. The 2DE and LC-MS/MS analysis were used for protein identification of differentially expressed proteins. Furthermore, the quantitation of gene expression was demonstrated using RT-qPCR. TIMER, HPA, and UALCAN databases were utilized for further analysis.</p><p><strong>Results: </strong>Differentially expressed proteins and genes after ML364 treatment in TNBC were found to be linked with the USP2 (ubiquitin specific peptidase 2)-mediated pathway. Our results demonstrate that differentially identified proteins, including PPA1, TRIM68, and FBXO46, could be a potential prognostic biomarker for TNBC. Further analysis through the UALCAN and HPA databasess showsthe high expression of these proteins in primary breast tumors, which is in contrast to normal. The induction of ML364 significantly reduced the expression of PPA1, TRIM68, and FBXO46 proteins and induced cell cytotoxicity in TNBC cells.</p><p><strong>Conclusion: </strong>This study provides an understanding of the USP2-mediated signaling pathway in TNBC, emphasizing the role of USP2 and its substrates with apoptotic genes. Our results offer insight into the USP2-mediated cellular mechanism after ML364 treatment in TNBC that could be a potential therapeutic candidate.</p>","PeriodicalId":10859,"journal":{"name":"Current protein & peptide science","volume":" ","pages":""},"PeriodicalIF":1.9000,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current protein & peptide science","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.2174/0113892037334325241014053319","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer with a high recurrence rate. A new therapeutic intervention is urgently needed to combat this lethal subtype. The identification of biomarkers is also crucial for improving outcomes in TNBC.
Method: The cell cytotoxicity of ML364 (2-(4-Methylphenylsulfonamido)-N-(4-phenylthiazol- 2-yl)-4-(trifluoromethyl)benzamide) was measured at different concentrations of ML364 in TNBC-treated and untreated cells. The 2DE and LC-MS/MS analysis were used for protein identification of differentially expressed proteins. Furthermore, the quantitation of gene expression was demonstrated using RT-qPCR. TIMER, HPA, and UALCAN databases were utilized for further analysis.
Results: Differentially expressed proteins and genes after ML364 treatment in TNBC were found to be linked with the USP2 (ubiquitin specific peptidase 2)-mediated pathway. Our results demonstrate that differentially identified proteins, including PPA1, TRIM68, and FBXO46, could be a potential prognostic biomarker for TNBC. Further analysis through the UALCAN and HPA databasess showsthe high expression of these proteins in primary breast tumors, which is in contrast to normal. The induction of ML364 significantly reduced the expression of PPA1, TRIM68, and FBXO46 proteins and induced cell cytotoxicity in TNBC cells.
Conclusion: This study provides an understanding of the USP2-mediated signaling pathway in TNBC, emphasizing the role of USP2 and its substrates with apoptotic genes. Our results offer insight into the USP2-mediated cellular mechanism after ML364 treatment in TNBC that could be a potential therapeutic candidate.
背景：三阴性乳腺癌（TNBC）是一种高复发率的侵袭性乳腺癌。迫切需要一种新的治疗干预措施来对抗这种致命的亚型。生物标志物的鉴定对于改善TNBC的预后也至关重要。方法：测定不同浓度ML364（2-（4-甲基苯基磺酰胺）- n -（4-苯基噻唑- 2-基）-4-（三氟甲基）苯甲酰胺）对tnbc处理和未处理细胞的细胞毒性。采用2DE和LC-MS/MS对差异表达蛋白进行蛋白鉴定。此外，利用RT-qPCR验证了基因表达的定量。使用TIMER、HPA和UALCAN数据库进行进一步分析。结果：发现ML364治疗TNBC后差异表达的蛋白和基因与USP2（泛素特异性肽酶2）介导的途径有关。我们的研究结果表明，包括PPA1、TRIM68和FBXO46在内的差异鉴定蛋白可能是TNBC的潜在预后生物标志物。通过UALCAN和HPA数据库的进一步分析显示，这些蛋白在原发性乳腺肿瘤中的高表达与正常相比。ML364的诱导显著降低了TNBC细胞中PPA1、TRIM68和FBXO46蛋白的表达，并诱导了细胞毒性。结论：本研究揭示了USP2在TNBC中介导的信号通路，强调了USP2及其底物在凋亡基因中的作用。我们的研究结果揭示了ML364治疗TNBC后usp2介导的细胞机制，这可能是一种潜在的治疗候选药物。
期刊介绍：
Current Protein & Peptide Science publishes full-length/mini review articles on specific aspects involving proteins, peptides, and interactions between the enzymes, the binding interactions of hormones and their receptors; the properties of transcription factors and other molecules that regulate gene expression; the reactions leading to the immune response; the process of signal transduction; the structure and function of proteins involved in the cytoskeleton and molecular motors; the properties of membrane channels and transporters; and the generation and storage of metabolic energy. In addition, reviews of experimental studies of protein folding and design are given special emphasis. Manuscripts submitted to Current Protein and Peptide Science should cover a field by discussing research from the leading laboratories in a field and should pose questions for future studies. Original papers, research articles and letter articles/short communications are not considered for publication in Current Protein & Peptide Science.
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