Pankreas epitel hücrelerinin onkojenik transformasyonunda PFKFB2'nin rolü
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Date
2018-10-18
Authors
Özcan, Selahattin Can
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Publisher
Uludağ Üniversitesi
Abstract
Pankreas duktal adenokarsinomu (PDA), tedavi seçeneklerinin sınırlı kaldığı ölümcül kanser türlerinin başında gelmektedir. PDA'ların yaklaşık %90'ında KRAS onkogeninin aktive edici mutasyonları görülmektedir. Bu durum KRAS'ın PDA oluşumundaki önemini ortaya koymaktadır. Mutant K-Ras'ın fonksiyonel aracılığını yapan gen ürünlerinin ortaya koyulması hem PDA biyolojisinin daha iyi anlaşılmasını, hem de bu ölümcül kanserin tedavisine yönelik alternatif moleküler hedeflerin belirlenmesini sağlayabilir. 6-fosfofrukto-2-kinaz/fruktoz-2,6-bisfosfataz (PFKFB) ailesine ait çift fonksiyonlu enzimler dört farklı gen tarafından (PFKFB1, PFKFB2, PFKFB3 ve PFKFB4) kodlanmakta ve hücre içi fruktoz-2,6-bisfosfat (Fru-2,6-BP) molekülünün yapım ve yıkımını sağlamaktadırlar. Fru-2,6-BP, glikolitik geçitin hız sınırlayıcı enzimlerinden olan 6-fosfofrukto-1-kinaz (PFK1)'ın bilinen en kuvvetli allosterik aktivatörüdür. Birçok tümör hücresinde birlikte eksprese edilen PFKFB proteinleri (PFKFB2, PFKFB3 ve PFKFB4) arasında PFKFB2, kanser hücre biyolojisinde en az çalışılan izoformdur. Bu çalışmada ilk defa PFKFB2'nin farklı kanser hücre hatlarında ekspresyonu karşılaştırılarak hücre nükleusuna lokalizasyonu ve PFKFB2 mRNA varyantlarının farklı oranlarda nükleusa lokalize olduğu tespit edildi. Pankreatik duktal epitel hücrelerinin mutant KRAS ekspresyonu ile gerçekleşen onkojenik transformasyonunda ve mutant KRAS bulundurduğu bilinen pankreatik duktal adenokarsinoma hücrelerinde PFKFB2'nin glikolitik fenotipe ve onkojenik özellikler üzerine etkisi incelendi. Elde edilen bulgulara göre pankreas kanserlerinde PFKFB2'nin onkojenik özellikleri ve glikolizi desteklediği görüldü. Sonuç olarak, PFKFB2 pankreatik hücre adenokarsinomalarının glikolitik fenotiplerinde ve onkojenik özelliklerinde önemlidir ve PFKFB2 pankreatik adenokarsinoma tedavisinde moleküler bir ilaç hedefi olarak değerlendirilebilir.
Pancreatic ductal adenocarcinoma (PDA) is one of the leading lethal malignacies with few therapeutic options. Ninety percent of PDA cases are characterized by an activating mutation in the KRAS oncogene. The fact that these mutations are detected in early phases of the molecular evolution of the disease progression suggests a key role for the K-Ras gene in oncogenic transformation of pancreatic duct cells. Discovery of gene products that mediate the effects of mutant K-Ras will not only help us better understand the biology of PDA but may also lead to the identification of novel molecular targets that may be utilized for the development of therapeutics against this deadly disease. The family of the bifunctional enzymes known as 6-phosphofructo-2- kinase/fructose-2,6-bisphosphatases (PFKFB) are encoded by four distinct genes (PFKFB1, PFKFB2, PFKFB3 and PFKFB4) and is responsible for production and degradation of fructose-2,6-bisphosphate (Fru-2,6-BP). Fru-2,6-BP is the most potent allosteric activator of 6-phosphofructo-1-kinase (PFK1), one of the rate-limiting enzymes of glycolysis. PFKFB2 is the least studied member of the PFKFB isozymes that are co-expressed in tumor cells (PFKFB2, PFKFB3 ve PFKFB4). In this study, expression of PFKFB2 in different cancer cell lines was compared and nuclear localization of PFKFB2 was determined for the first time. It was observed that 2 mRNA variants of PFKFB2 have different nuclear localization ratios. Effects of PFKFB2 on glycolytic phenotype and oncogenic capabilities was investigated in mutant KRAS driven oncogenic transformation of pancreatic ductal epithelia cells and mutant KRAS harboring pancreatic adenocarcinoma cells. According to recent findings, it was observed that PFKFB2 supports oncogenic and glycolytic features of pancreatic cancers. In conclusion, PFKFB2 is important for the oncogenic characteristics and glycolytic phenotype of pancreatic adenocarcinomas and PFKFB2 could be considered as a molecular drug target for the treatment of pancreatic adenocarcinoma. Keywords: PFKFB2, KRAS, Pancreatic ductal adenocarcinoma, Fructose-2,6- bisphosphate, Oncogenic transformation
Pancreatic ductal adenocarcinoma (PDA) is one of the leading lethal malignacies with few therapeutic options. Ninety percent of PDA cases are characterized by an activating mutation in the KRAS oncogene. The fact that these mutations are detected in early phases of the molecular evolution of the disease progression suggests a key role for the K-Ras gene in oncogenic transformation of pancreatic duct cells. Discovery of gene products that mediate the effects of mutant K-Ras will not only help us better understand the biology of PDA but may also lead to the identification of novel molecular targets that may be utilized for the development of therapeutics against this deadly disease. The family of the bifunctional enzymes known as 6-phosphofructo-2- kinase/fructose-2,6-bisphosphatases (PFKFB) are encoded by four distinct genes (PFKFB1, PFKFB2, PFKFB3 and PFKFB4) and is responsible for production and degradation of fructose-2,6-bisphosphate (Fru-2,6-BP). Fru-2,6-BP is the most potent allosteric activator of 6-phosphofructo-1-kinase (PFK1), one of the rate-limiting enzymes of glycolysis. PFKFB2 is the least studied member of the PFKFB isozymes that are co-expressed in tumor cells (PFKFB2, PFKFB3 ve PFKFB4). In this study, expression of PFKFB2 in different cancer cell lines was compared and nuclear localization of PFKFB2 was determined for the first time. It was observed that 2 mRNA variants of PFKFB2 have different nuclear localization ratios. Effects of PFKFB2 on glycolytic phenotype and oncogenic capabilities was investigated in mutant KRAS driven oncogenic transformation of pancreatic ductal epithelia cells and mutant KRAS harboring pancreatic adenocarcinoma cells. According to recent findings, it was observed that PFKFB2 supports oncogenic and glycolytic features of pancreatic cancers. In conclusion, PFKFB2 is important for the oncogenic characteristics and glycolytic phenotype of pancreatic adenocarcinomas and PFKFB2 could be considered as a molecular drug target for the treatment of pancreatic adenocarcinoma. Keywords: PFKFB2, KRAS, Pancreatic ductal adenocarcinoma, Fructose-2,6- bisphosphate, Oncogenic transformation
Description
Keywords
PFKFB2, KRAS, Pankreatik duktal adenokarsinoma, Fruktoz 2-6-bisfosfat, Onkojenik transformasyon, Oncogenic transformation, PFKFB2, KRAS, Pancreatic ductal adenocarcinoma, Fructose-2,6- bisphosphate
Citation
Özcan, S. C. (2018). Pankreas epitel hücrelerinin onkojenik transformasyonunda PFKFB2'nin rolü. Yayınlanmamış doktora tezi. Uludağ Üniversitesi Sağlık Bilimleri Enstitüsü.