Nilotinib Exerts a Therapeutic Approach via JAK/STAT Pathway and Cytokine Network in Chronic Myeloid Leukemia Cells

Tunzala Yavuz; Burçin Tezcanlı Kaymaz; Besne Çelik; Leila Sabour Takanlou; İlayda Alçıtepe; Maryam Sabour Takanlou; Çığır Avcı; Nur Selvi Günel; Nur Soyer; Fahri Şahin; Güray Saydam

doi:10.19161/etd.1215481

TR EN

Nilotinib, Kronik Miyeloid Lösemi Hücrelerinde JAK/STAT Yolu ve Sitokin Ağı Üzerinden Terapötik Bir Yaklaşım Uygular

Öz

Amaç: Kronik miyeloid lösemi (KML), çeşitli sinyal yollarının aktivasyonuna ve lösemik fenotipin sonucuna yol açan yapıcı bir tirozin kinaz (TK) aktivitesi gösterir. JAK/STAT yolundan aktive edilmiş STAT5A ve STAT5B, bir sitokin ağı tarafından teşvik edilen lösemik hücrelerin büyümesini, çoğalmasını, farklılaşmasını ve hayatta kalmasını indükler. İkinci nesil tirozin kinaz inhibitörü nilotinib, bu onkojenik TK aktivitesini inhibe etme avantajına sahip olduğundan; terapötik yaklaşımının altında yatan mekanizmayı ve yolun gelecekteki moleküler hedeflerini analiz ederek apoptozu nasıl indüklediğini araştırmayı amaçladık. Yöntem: Nilotinib tedavileri ile hücre canlılığı ve proliferasyon deneyleri, apoptotik analiz, STAT5A&5B mRNA transkriptlerinin ekspresyonel düzenlemeleri, protein ekspresyon seviyeleri ve ayrıca sitokinlerin ekspresyonel değerlendirmeleri, in vitro olarak CML model K562 hücrelerinde belirlendi. Sonuç: Nilotinib tedavisi, zamana ve doza bağlı bir şekilde lösemik hücre proliferasyonunu ve sağkalımını azaltarak terapötik bir yaklaşımı değerlendirdi; lösemik hücre apoptozunu indüklemek, STAT5A&5B mRNA'yı aşağı regüle etmek ve protein ekspresyon seviyelerini düzenlemek ve sitokin ekspresyon ağını düzenlemek. Çözüm: Nilotinib aracılı terapötikler, JAK/STAT yolu üyeleri STAT5A ve STAT5B'nin hedeflenmesine bağlı olabilir, ayrıca; sitokin ağının düzenlenmesi, lösemi patogenezinde K562 hücrelerinin nilotinibe duyarlılığı ve tepkisi için başka bir altta yatan mekanizma olabilir.

Anahtar Kelimeler

Nilotinib Exerts a Therapeutic Approach via JAK/STAT Pathway and Cytokine Network in Chronic Myeloid Leukemia Cells

Abstract

Aim: Chronic myeloid leukemia (CML) displays a constitutive tyrosine kinase (TK) activity which in turn leads to the activation of various signaling pathways and the outcome of leukemic phenotype. Activated STAT5A and STAT5B from JAK/STAT pathway induce cell growth, proliferation, differentiation, and survival of leukemic cells which are promoted by a cytokine network. Since the second-generation tyrosine kinase inhibitor nilotinib has the advantage of inhibiting this oncogenic TK activity; we aimed to investigate the underlying mechanism of its therapeutic approach and how it induced apoptosis via analyzing the forthcoming molecular targets of the pathway. Methods: By Nilotinib treatments, cell viability and proliferation assays, apoptotic analysis, expressional regulations of STAT5A&5B mRNA transcripts, protein expression levels, and also cytokines’ expressional assessments were determined in CML model K562 cells, in vitro. Results: Nilotinib treatment in a time and dose-dependent manner assessed a therapeutic approach by decreasing leukemic cell proliferation and survival; inducing leukemic cell apoptosis, down-regulating STAT5A&5B mRNA, and protein expression levels, and regulating cytokine expressional network. Conclusion: Nilotinib-mediated therapeutics could be dependent on targeting JAK/STAT pathway members STAT5A and STAT5B, besides; regulating the cytokine network might be another underlying mechanism for sensitization and response of K562 cells to nilotinib in leukemia pathogenesis.

Keywords

References

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Details

Primary Language

English

Subjects

Health Care Administration

Journal Section

Research Article

Authors

Tunzala Yavuz
0000-0002-6750-2967
Türkiye

Burçin Tezcanlı Kaymaz ^*
0000-0003-1832-1454
Palestine

Besne Çelik
0000-0001-5417-8005
Türkiye

Leila Sabour Takanlou
0000-0002-6361-7150
Türkiye

İlayda Alçıtepe
0000-0002-7548-9248
Türkiye

Maryam Sabour Takanlou
0000-0002-1590-4833
Türkiye

Çığır Avcı
0000-0002-2748-3124
Türkiye

Nur Selvi Günel
0000-0003-0612-2263
Türkiye

Nur Soyer
0000-0002-7722-506X
Türkiye

Fahri Şahin
0000-0001-9315-8891
Türkiye

Güray Saydam
0000-0001-8646-1673
Türkiye

Publication Date

March 19, 2024

Submission Date

December 7, 2022

Acceptance Date

August 31, 2023

Published in Issue

Year 2024 Volume: 63 Number: 1

DOI

https://doi.org/10.19161/etd.1215481

IZ

https://izlik.org/JA43BA88MW

Cite

RIS / Bibtex

Vancouver

1.Tunzala Yavuz, Burçin Tezcanlı Kaymaz, Besne Çelik, Leila Sabour Takanlou, İlayda Alçıtepe, Maryam Sabour Takanlou, Çığır Avcı, Nur Selvi Günel, Nur Soyer, Fahri Şahin, Güray Saydam. Nilotinib Exerts a Therapeutic Approach via JAK/STAT Pathway and Cytokine Network in Chronic Myeloid Leukemia Cells. EJM. 2024 Mar. 1;63(1):124-35. doi:10.19161/etd.1215481