Role of PFKFB2 in the oncogenic transformation of pancreatic epithelial cells

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