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Meme kanseri kadınlarda en yaygın gözlenen kanser türüdür. Mevcut tedavilerin düşük seçicilik ya da zamanla oluşan ilaç direnci gibi eksiklerini giderebilecek yeni stratejilerin belirlenmesine ihtiyaç vardır. Çalışmamızda, çoklu hedefli bir tirozin kinaz inhibitörü olan ponatinibin meme kanseri hücreleri üzerindeki anti-kanser etkisini değerlendirmeyi ve ponatinib yanıtında yer alan miRNA'ların biyoinformatik yaklaşım ile sinyal yolaklarındaki potansiyel işlevini tanımlamayı hedefledik. Bu amaçla, MCF-7 hücrelerinde ponatinibin sitotoksik etkileri xCELLigence ile gerçek-zamanlı olarak belirlendi. Ponatinib uygulaması sonrasında apoptoz, proliferasyon hızı, hücre döngüsündeki değişimler akım sitometriyle, miRNA'ların ifadelerindeki düzenlenmeler qRT-PCR ile değerlendirildi. İfadelerinde anlamlı değişim belirlenen miRNA’ların ilişkili olduğu olası mRNA’lar ve sinyal yolakları KEGG yolak analizi ile tanımlandı. Ponatinibin MCF-7 hücreleri üzerinde sitotoksik etkiye sahip olduğu (IC50: 4,59 μM) belirlendi. Ponatinib uygulaması ile MCF-7 hücrelerinde anlamlı olarak apoptozun indüklendiği, proliferasyonun baskılandığı ve hücre döngüsünün G0/G1, S evrelerinde durakladığı belirlendi. Ayrıca, let-7a-5p, miR-29a-3p, miR-7-5p, miR-125b-5p, miR-212-3p ifadelerinde artış (p<0,05), miR-210-3p, miR-19b-3p, miR-140-5p, miR-181b-5p, miR-155-5p, miR-223-3p, miR-141-3p, miR-21-5p ifadelerinde azalma olduğu (p<0,05), miR-19a-3p ifadesinin ise tamamen baskılandığı belirlendi. Biyoinformatik analizler ile, ifadesi değişen miRNA’ların kanserde proteoglikanlar, Hippo, p53, TGF-beta, kanser-ilişkili, PI3K-Akt, prolaktin, hücre döngüsü, östrojen, mTOR sinyal yolakları ile ilişkili olduğu ortaya koyuldu. Ponatinib uygulaması meme kanseri hücrelerinde apoptozu indükleyerek, proliferasyonu baskılayarak ve hücre döngüsünü durdurarak güçlü anti-kanser aktivite sergilemiştir. Ponatinibin belirlenen anti-kanser etkilerinde miRNA’ların rolleri olabileceği gösterilmiştir. Olası miRNA-mRNA etkileşimleri ile meme kanserindeki hedef sinyal yolaklarının tanımlanması ışığında, ponatinibin tek başına veya diğer tedavilerle kombinasyon halinde meme kanseri tedavisi için potansiyel bir strateji olabileceği görüşündeyiz.
Breast cancer is the most commonly observed type of cancer in women. It is necessary to identify new strategies that can address the deficiencies of existing treatments, such as low selectivity or time-making drug resistance. In our study, we aimed at evaluating the anti-cancer effect of ponatinibin, a multi-target thyrozyne kinase inhibitor on breast cancer cells and identifying the potential function of myRNAs in ponatinib response with the bioinformatic approach and in the signal pathways. For this purpose, the cytotoxic effects of ponatinibin in MCF-7 cells were determined in real-time with xCELLigence. After the application of Ponatinib, apoptosis, the rate of proliferation, changes in the cell cycle were assessed by the flow cytometry, the regulations in the expression of miRNAs were assessed by qRT-PCR. Significant changes in their statements were identified by the potential mRNAs and signal pathways in which determined miRNAs were associated with the KEGG path analysis. Ponatinibin has a cytotoxic effect on MCF-7 cells (IC50: 4,59 μM). The application of Ponatinib determined that apoptosis was significantly induced in the MCF-7 cells, that proliferation was suppressed and that the cell cycle stopped in the stages of G0/G1, S. Furthermore, there was a decrease in let-7a-5p, miR-29a-3p, miR-7-5p, miR-125b-5p, miR-212-3p expression (p<0,05), miR-210-3p, miR-19b-3p, miR-140-5p, miR-181b-5p, miR-155-5p, miR-223-3p, miR-141-3p, miR-21-5p expression (p<0,05), and the expression of miR-19a-3p was completely printed. By bioinformatical analyses, the expression changes found that myRNAs in cancer were associated with proteoglycans, Hippo, p53, TGF-beta, cancer-related, PI3K-act, prolactin, cell cycle, estrogen, mTOR signals. The application of Ponatinib has shown strong anti-cancer activity by inducing apoptosis in breast cancer cells, suppressing proliferation and stopping the cell cycle. It has been shown that myRNAs may have roles in the determined anti-cancer effects of ponatinibin. In the light of the possible miRNA-mRNA interactions and the identification of target signal pathways in breast cancer, we believe that ponatinib alone or in combination with other treatments may be a potential strategy for the treatment of breast cancer.
Breast cancer is the most common cancer in women. There is a need to identify novel strategies that can overcome the failure of existing treatments, such as low selectivity or drug-resistance. In our study, we aimed to evaluate the anti-cancer effect of ponatinib, a multi-targeted tyrosine kinase inhibitor, on breast cancer cells and to define the potential function of miRNAs involved in the ponatinib response in signaling pathways with bioinformatics analysis. For this purpose, the cytotoxic effects of ponatinib on MCF-7 cells were measured in real-time by xCELLigence. After ponatinib treatment, changes in apoptosis, proliferation, cell-cycle regulation were evaluated by flow cytometry, and the regulations of miRNAs were evaluated by qRT-PCR. mRNAs and signaling pathways interacted with miRNAs that significantly changed were predicted by KEGG pathway analysis. It was determined that ponatinib had a cytotoxic effect (IC50: 4.59 μM) on MCF-7 cells. After ponatinib treatment, it was determined that apoptosis was induced, proliferation was suppressed and the cell-cycle was arrested at the G0/G1 and S phases significantly in MCF-7 cells. Ponatinib up-regulated let-7a-5p, miR-29a-3p, miR-7-5p, miR-125b-5p, miR-212-3p expressions (p<0,05). Following the ponatinib exposure, miR-210-3p, miR-19b-3p, miR-140-5p, miR-181b-5p, miR-155-5p, miR-223-3p, miR-141-3p, miR-21-5p were down-regulated (p<0,05) while the expression of miR-19a-3p was completely suppressed. Bioinformatics analyzes revealed that ponatinib-regulated miRNAs are associated with proteoglycans in cancers, Hippo, p53, TGF-beta, cancer-related, PI3K-Akt, prolactin, cell-cycle, estrogen, mTOR signaling pathways. Ponatinib treatment exhibited potent anti-cancer activity by inducing apoptosis, suppressing proliferation and blocking the cell-cycle progression in breast cancer cells. It has been shown that miRNAs play roles in the anti-cancer efficiency of ponatinib. In light of the identification of target signaling pathways based on the predicted miRNA-mRNA interactions, we believe that ponatinib alone or in combination with other treatments may be a potential strategy for the treatment of breast cancer.
Alan : Sağlık Bilimleri
Dergi Türü : Ulusal
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