Browsing by Author "Iglesias, Alberto A."
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Publication PFKFB2 regulates glycolysis and proliferation in pancreatic cancer cells(Springer, 2020-05-15) Özcan, Selahattin C.; Sarıoğlu, Aybike; Altunok, Tuğba H.; Akkoç, Ahmet; Güzel, Saime; Güler, Sabire; Imbert-Fernandez, Yoannis; Muchut, Robertino J.; Iglesias, Alberto A.; Gürpınar, Yunus; Clem, Amy L.; Chesney, Jason A.; Yalçın, Abdullah; Sarıoğlu, Aybike; Altunok, Tuğba H.; AKKOÇ, AHMET; GÜZEL, SAİME; GÜLER, SABİRE; Gürpınar, Yunus; YALÇIN, ABDULLAH; Bursa Uludağ Üniversitesi/Veteriner Fakültesi/Biyokimya Anabilim Dalı.; Bursa Uludağ Üniversitesi/Veteriner Fakültesi/Patoloji Anabilim Dalı.; Bursa Uludağ Üniversitesi/Veteriner Fakültesi/Histoloji ve Embriyoloji Anabilim Dalı.; 0000-0002-8287-6617; 0000-0003-1263-3799; 0000-0003-0796-5000; 0000-0002-7698-0872; 0000-0001-8519-8375; S-2474-2018; GCY-0775-2022; DTZ-3578-2022; AAH-4275-2021; HNI-3945-2023; ABI-4164-2020Tumor cells increase glucose metabolism through glycolysis and pentose phosphate pathways to meet the bioenergetic and biosynthetic demands of rapid cell proliferation. The family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) are key regulators of glucose metabolism via their synthesis of fructose-2,6-bisphosphate (F2,6BP), a potent activator of glycolysis. Previous studies have reported the co-expression of PFKFB isozymes, as well as the mRNA splice variants of particular PFKFB isozymes, suggesting non-redundant functions. Majority of the evidence demonstrating a requirement for PFKFB activity in increased glycolysis and oncogenic properties in tumor cells comes from studies on PFKFB3 and PFKFB4 isozymes. In this study, we show that the PFKFB2 isozyme is expressed in tumor cell lines of various origin, overexpressed and localizes to the nucleus in pancreatic adenocarcinoma, relative to normal pancreatic tissue. We then demonstrate the differential intracellular localization of two PFKFB2 mRNA splice variants and that, when ectopically expressed, cytoplasmically localized mRNA splice variant causes a greater increase in F2,6BP which coincides with an increased glucose uptake, as compared with the mRNA splice variant localizing to the nucleus. We then show that PFKFB2 expression is required for steady-state F2,6BP levels, glycolytic activity, and proliferation of pancreatic adenocarcinoma cells. In conclusion, this study may provide a rationale for detailed investigation of PFKFB2's requirement for the glycolytic and oncogenic phenotype of pancreatic adenocarcinoma cells.Publication Simultaneous inhibition of PFKFB3 and GLS1 selectively kills KRAS transformed pancreatic cells(Academic Press, 2021-09-24) Özcan, Selahattin C.; Mutlu, Aydan; Altunok, Tuğba H.; Gürpınar, Yunus; Sarıoğlu, Aybike; Güler, Sabire; Muchut, Robertino J.; Iglesias, Alberto A.; Çelikler, Serap; Campbell, Paul M.; Yalçın, Abdullah; GÜLER, SABİRE; ÇELİKLER KASIMOĞULLARI, SERAP; YALÇIN, ABDULLAH; Mutlu, Aydan; Altunok, Tuğba H.; Sarıoğlu, Aybike; 0000-0003-1263-3799; 0000-0002-8287-6617; 0000-0002-4177-3478; 0000-0001-8519-8375; FNG-9051-2022; GCY-0775-2022; S-2474-2018; HTY-9355-2023; JCD-5015-2023; ABI-4164-2020Activating mutations of the oncogenic KRAS in pancreatic ductal adenocarcinoma (PDAC) are associated with an aberrant metabolic phenotype that may be therapeutically exploited. Increased glutamine utilization via glutaminase-1 (GLS1) is one such feature of the activated KRAS signaling that is essential to cell survival and proliferation; however, metabolic plasticity of PDAC cells allow them to adapt to GLS1 inhibition via various mechanisms including activation of glycolysis, suggesting a requirement for combinatorial anti-metabolic approaches to combat PDAC. We investigated whether targeting the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) in combination with GLS1 can selectively prevent the growth of KRAS-transformed cells. We show that KRAStransformation of pancreatic duct cells robustly sensitizes them to the dual targeting of GLS1 and PFKFB3. We also report that this sensitivity is preserved in the PDAC cell line PANC-1 which harbors an activating KRAS mutation. We then demonstrate that GLS1 inhibition reduced fructose-2,6-bisphosphate levels, the product of PFKFB3, whereas PFKFB3 inhibition increased glutamine consumption, and these effects were augmented by the co-inhibition of GLS1 and PFKFB3, suggesting a reciprocal regulation between PFKFB3 and GLS1. In conclusion, this study identifies a novel mutant KRAS-induced metabolic vulnerability that may be targeted via combinatorial inhibition of GLS1 and PFKFB3 to suppress PDAC cell growth. (c) 2021 Published by Elsevier Inc.Publication Transforming growth factor β1 upregulates 6‐phosphofructo‐ 2‐kinase/fructose 2,6‐bisphosphatase‐4 expression in A549 and MCF‐10A cells(Wiley, 2023-09-04) Altunok, Tuğba H.; Muchut, Robertino J.; Iglesias, Alberto A.; Yalçın, Abdullah; Altunok, Tuğba H.; YALÇIN, ABDULLAH; Bursa Uludağ Üniversitesi/Veterinerlik Fakültesi/Biyokimya Anabilim Dalı.; 0000-0003-1263-3799 ; KMY-2643-2024; JTP-1429-2023Transforming growth factor beta 1 (TGF beta 1) induces a cellular process known as epithelial-mesenchymal transition (EMT) associated with metabolic reprogramming, including enhanced glycolysis. Given the involvement of 6-phosphofructo-2-kinase/ fructose 2,6-bisphosphatase (PFKFB) enzymes in glycolysis, we aimed to investigate whether TGF beta 1 regulates expressions of PFKFB genes and if PFKFBs are required for TGF beta 1-driven phenotypes. A549 and MCF-10A cell lines were used as TGF beta 1driven EMT models. Messenger RNA expressions of PFKFB and EMT genes were determined by real-time quantitative polymerase chain reaction. A small interfering RNA approach was used to deplete PFKFB4 expression. A Matrigel invasion assay was conducted to assess the effect of PFKFB4 silencing on the TGF ss 1-enhanced invasion of A549 cells. F2,6BP levels were analyzed using an enzyme-coupled assay. Glucose and lactate concentrations were determined using colorimetric assays. TGF beta 1 robustly induced expression of the fourth isoform of PFKFBs, PFKFB4, in both cell lines. PFKFB4 depletion partially inhibits mesenchymal transdifferentiation caused by TGF beta 1 in A549 cells, as assessed by microscopy. Inductions of Snail in MCF-10A cells and Fibronectin in A549 cells and repressions of E-cadherin in both cell lines by TGF beta 1 are attenuated by PFKFB4 silencing. PFKFB4 silencing reduces F2,6BP and glycolytic activity, although TGF beta 1 alone does not affect these parameters. Finally, PFKFB4 depletion suppresses the TGF beta 1-driven invasion of A549 cells through Matrigel. Presented data suggest that TGF ss 1 induces the expression of PFKFB4 in A549 and MCF-10 cells, and PFKFB4 may be required for TGF beta 1-driven phenotypes such as EMT and invasion in these models.