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ÇELİKLER KASIMOĞULLARI, SERAP

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ÇELİKLER KASIMOĞULLARI

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    Palladium (II) complex enhances ROS-dependent apoptotic effects via autophagy inhibition and disruption of multiple signaling pathways in colorectal cancer cells
    (Bentham Science Publ Ltd, 2021-01-01) Aydınlık, Şeyma; Erkısa, Merve; Arı, Ferda; Çelikler, Serap; Ulukaya, Engin; Aydınlık, Şeyma; ARI, FERDA; ÇELİKLER KASIMOĞULLARI, SERAP; 0000-0001-5238-2432; 0000-0002-6729-7908; 0000-0002-4177-3478; ABI-2909-2020; AAG-7012-2021; JCD-5015-2023
    Background: Inhibition of autophagy is reported to be a therapeutically effective strategy in overcoming resistance that is a deadly outcome in cancer. One of the most common reasons for chemo-resistance to treatment is the patients with tumors exhibiting a KRAS mutation, which occurs in approximately 40% of colorectal cancer patients.Objective: Hence, we assessed whether a Palladium (Pd)(II) complex is a promising anticancer complex, compared to 5-fluorouracil in KRAS wt HT-29 and KRAS mutant HCT-15 cells.Methods: HCT-15 and HT-29 cells were used for colorectal cancer and Chloroquine (CQ) was used as an inhibitor of autophagy. In this context, cells were treated with Pd(II) complex and 5-FU in combination with CQ for 48h and cell viability was measured by SRB assay. Cell death mode was examined with M30 and M65 ELISA assays, using annexin V/propidium iodide. Autophagy was determined by Acridine Orange (AO) staining. Furthermore, the expressions of various autophagy and apoptosis-related proteins were evaluated with Western blotting. Luminex assay and the level of Reactive Oxygen Species (ROS) were examined.Results: Cell viability was found to decrease in a dose-dependent manner and CQ enhanced cytotoxic effect in Pd(II) and 5-FU treated cells in colorectal cancer cells. Our data showed that inhibition of autophagic flux significantly increased intrinsic apoptosis through the activation of ROS. We showed that combinatorial treatment with CQ induced apoptosis via the caspase-dependent mitochondrial pathway. Luminex analysis revealed that the combination resulted in a down-regulation of NF-?B/AKT/CREB signaling pathways in both cell lines, however, decreased Erk1/2 protein expression was only observed after treatment with CQ combination in HCT-15 cells.Conclusion: We suggest that the inhibition of autophagy along with Pd(II) and 5-FU treatment has a synergistic effect on KRAS-mutant colorectal cancer cells. Autophagy inhibition by CQ promotes apoptosis via blockade of the NF-?B/AKT/CREB and activation of ROS.
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    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-4164-2020
    Activating 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.