Kanser kök hücrelerinde PFKFB izoenzimlerinin rolü
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Date
2021-06-23
Authors
Gürpınar, Yunus
Journal Title
Journal ISSN
Volume Title
Publisher
Bursa Uludağ Üniversitesi
Abstract
Kanser kök hücre (KKH)’ler, tümör oluşumunu başlattığı ve mevcut tümör dokusunun oldukça küçük bir bölümünü oluşturduğu düşünülen, yenilenme kabiliyeti yüksek hücrelerdir. Normal kök hücrelerle benzer yüzey belirteçleri ve pluripotentlik markörlerine sahip olan ve bu özellikleri sayesinde tümör dokusunun kalanından ayrılabilen bu hücre topluluğu; radyoterapi ve kemoterapiye karşı yüksek direnç göstermekte, tedavi sürecinde yok edilemediklerinde tümörün yeniden şekillenmesine neden olmaktadır. KKH enerji metabolizması üzerine yapılan çalışmalar, birtakım belirteçlere göre profillendirilmiş KKH’ler hakkında bilgi verse de profilleme işleminin belirli bir standardı olmadığından, henüz kesin bir sonuca varmak mümkün olmamıştır. Glikoliz spesifik hız sınırlayıcı basamak olan PFK-1 enziminin aktivatörü olan fruktoz 2,6 bisfosfat’ın yapım ve yıkımı, 6-fosfofrukto-2-kinaz/fruktoz-2,6-bisfosfataz izoenzimleri (PFKFB1-4) tarafından gerçekleştirilmektedir. Tümör hücrelerinde; tümör tipine göre değişen seviyelerde eksprese edilen bu izoenzimlerin; KKH ile tümör kitlesini oluşturan farklılaşmış hücrelerdeki ekspresyonlarının farklı seviyelerde olduğu tespit edilmiştir. Bu çalışmada, meme kanseri hücre hattı MCF-7 ve pankreatik duktal adenokarsinom hücre hatları PANC-1 ve Mia PaCa-2’de; PFKFB izoenzimlerinin hücre popülasyonundaki KKH miktarı ile oranları belirlendi ve PFKFB baskılanmasının, KKH popülasyonu değişimi üzerindeki etkileri incelendi. Elde edilen bulgulara göre, PANC-1 ve Mia PaCa-2 hücre hatlarında KKH popülasyonu yüksek hücre gruplarında PFKFB1 ve PFKFB4 izoenzimi ekspresyonunun arttığı ve PFKFB4 baskılanması sonucu PANC-1 hücre hattında KKH popülasyonunun azaldığı görüldü. Baskılamanın, bütün hücre hatlarında onkojenik potansiyel üzerinde negatif yönde etkiye neden olmadığı tespit edildi. Elde edilen verilere göre; PFKFB4 izoenziminin, KKH'lerin idenfikasyonunda yol gösterici olabileceği ve ilerideki çalışmalar için moleküler bir ilaç hedefi olabileceği düşünülmektedir.
Cancer stem cells (CSC) are subset of tumor cells with high regenerative ability that are thought to initiate tumor formation; yet constitute a very small part of the existing tumor tissue. This rare cell population shares features with normal stem cells like cell surface markers and pluripotency factors, and can be separated from the rest of the tumor tissue by those features. CSCs shows high resistance to radiotherapy and chemotherapy, and if they could not be destroyed during the treatment process, tumor relapse might occur. There are some studies about energy metabolism gives information about metabolic profile of CSCs in different tissues and tumors. Still, there is no consensus about these metabolic profiles beacuse identification of CSCs differs a lot between different types of tissues and lacks standardization. Fructose 2,6 bisphosphate is an activator of glycolysis specific rate limiting enzyme PFK-1. Its formation and degradation is carried out by 6-phosphofructo-2-kinase / fructose-2,6-bisphosphatase isoenzymes (PFKFB1-4). These isoenzymes expressed in tumor cells at varying levels depending on the tumor type and their expression in CSCs and differentiated tumor cells are dissimilar. In this study, rates of PFKFB isoenzymes and CSC percentage in the cell populations was examined in breast cancer cell line MCF-7 and pancreatic ductal adenocarcinoma cell lines PANC-1 and Mia PaCa-2, to identify a possible correlation. Also, effects of PFKFB suppression on CSC population were examined. Results indicate that expression of PFKFB1 and PFKFB4 isoenzymes increased in the cell groups with high CSC population in PANC-1 and Mia PaCa-2 cell lines, and CSC population decreased in PANC-1 cell line as a result of PFKFB4 suppression. It was found that suppression did not cause any negative effects on the oncogenic potential in all cell lines. According to the data obtained; It is thought that difference in PFKFB4 isoenzyme levels could be a marker of CSCs. Also, PFKFB4 might be selected as a molecular drug target for future studies.
Cancer stem cells (CSC) are subset of tumor cells with high regenerative ability that are thought to initiate tumor formation; yet constitute a very small part of the existing tumor tissue. This rare cell population shares features with normal stem cells like cell surface markers and pluripotency factors, and can be separated from the rest of the tumor tissue by those features. CSCs shows high resistance to radiotherapy and chemotherapy, and if they could not be destroyed during the treatment process, tumor relapse might occur. There are some studies about energy metabolism gives information about metabolic profile of CSCs in different tissues and tumors. Still, there is no consensus about these metabolic profiles beacuse identification of CSCs differs a lot between different types of tissues and lacks standardization. Fructose 2,6 bisphosphate is an activator of glycolysis specific rate limiting enzyme PFK-1. Its formation and degradation is carried out by 6-phosphofructo-2-kinase / fructose-2,6-bisphosphatase isoenzymes (PFKFB1-4). These isoenzymes expressed in tumor cells at varying levels depending on the tumor type and their expression in CSCs and differentiated tumor cells are dissimilar. In this study, rates of PFKFB isoenzymes and CSC percentage in the cell populations was examined in breast cancer cell line MCF-7 and pancreatic ductal adenocarcinoma cell lines PANC-1 and Mia PaCa-2, to identify a possible correlation. Also, effects of PFKFB suppression on CSC population were examined. Results indicate that expression of PFKFB1 and PFKFB4 isoenzymes increased in the cell groups with high CSC population in PANC-1 and Mia PaCa-2 cell lines, and CSC population decreased in PANC-1 cell line as a result of PFKFB4 suppression. It was found that suppression did not cause any negative effects on the oncogenic potential in all cell lines. According to the data obtained; It is thought that difference in PFKFB4 isoenzyme levels could be a marker of CSCs. Also, PFKFB4 might be selected as a molecular drug target for future studies.
Description
Keywords
Kanser kök hücre (KKH), 6-fosfofrukto-2-kinaz /fruktoz 2,6-bisfosfataz (PFKFB), Kanser metabolizması, Cancer stem cell (CSC), 6-phosphofructo-2-kinase / fructose-2,6-bisphosphatase isoenzymes (PFKFB), Cancer metabolism
Citation
Gürpınar, Y. (2021). Kanser kök hücrelerinde PFKFB izoenzimlerinin rolü. Yayınlanmamış doktora tezi. Bursa Uludağ Üniversitesi Sağlık Bilimleri Enstitüsü.