Scopus İndeksli Yayınlar Koleksiyonu
Permanent URI for this collectionhttps://hdl.handle.net/11727/4809
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Item Kinome-wide RNAi screening for mediators of ABT-199 resistance in breast cancer cells identifies Wee1 as a novel therapeutic target(2021) Aka, Yeliz; Acikbas, Ufuk; Kutuk, Ozgur; 34171479Antiapoptotic and proapoptotic BCL-2 protein family members regulate mitochondrial apoptotic pathway. Small molecule inhibitors of antiapoptotic BCL-2 proteins including BCL-2-specific inhibitor ABT-199 (Venetoclax) are in clinical development. However, the efficiency of ABT-199 as a single agent in solid tumors is limited. We performed a high-throughput RNAi kinome screen targeting 691 kinases to identify potentially targetable kinases to enhance ABT-199 response in breast cancer cells. Our studies identified Wee1 as the primary target kinase to overcome resistance to ABT-199. Depletion of Wee1 by siRNA-mediated knockdown or inhibition of Wee1 by the small molecule Wee1 inhibitor AZD1775 sensitized SKBR3, MDA-MB-468, T47D and CAMA-1 breast cancer cells to ABT-199 along with decreased MCL1. BH3-only proteins PUMA and BIM functionally contribute to apoptosis signaling following co-targeting BCL-2 and Wee1. Suppression of Wee1 function increased mitochondrial cell death priming. Furthermore, we found that Wee1 inhibition altered MCL1 phosphorylation and protein stability, which led to HUWE1-mediated MCL1 degradation. Our findings suggest that Wee1 inhibition can overcome resistance to ABT-199 and provide a rationale for further translational investigation of BCL-2 inhibitor/Wee1 inhibitor combination in breast cancer.Item Novel inflammatory targets for immunotherapies in pediatric patients with trichotillomania(2020) Kutuk, Meryem Ozlem; Tufan, Ali Evren; Kilicaslan, Fethiye; Mutluer, Tuba; Gokcen, Cem; Karadag, Mehmet; Yektas, Cigdem; Kandemir, Hasan; Buber, Ahmet; Aksu, Gulen Guler; Topal, Zehra; Giray, Asli; Celik, Fatma; Acikbas, Ufuk; Kutuk, Ozgur; 0000-0002-2918-7871; 32113788; AAI-9626-2021Immune dysregulation may be important in the etiology of obsessive-compulsive and related disordersandbody-focusedrepetitivebehaviors, such as Trichotillomania (TTM). The role of inflammation and inflammatory markers in TTM has received relatively little attention. This study was aimed to determine the expression levels of inflammatory markers (i.e. IL-1 beta, IL-1 alpha, IL-4, IL-6, IL-17, TNF-alpha and TGF-5) in peripheral blood mononuclear cells of children with TTM and healthy controls and to evaluate their association with clinical variables. Seventy-seven patients with TTM and 107 healthy controls were enrolled in the study. Peripheral blood was collected in standardized conditions. The mean age of patients and controls did not differ significantly (10.8 +/- 4.4 and 12.0 +/- 3.2 years; respectively). The majority of patients with TTM and controls were females (n = 55, 71.4 % and n = 55, 51.4 %; respectively); with a greater preponderance of females among TTM. Patients with TTM had significantly elevated expression levels of TNF-alpha, IL-6 and IL-17 compared to controls. However, the expression level of IL-4 was significantly reduced in TTM patients compared to controls. Accordingly, we found a proinflammatory state in TTM and those findings may suggest novel treatment options for TTM and further, crossdisciplinary studies focusing on neuro- inflammation in TTM conducted on larger samples are needed.Item Cytokine expression profiles in Autism spectrum disorder: A multi-center study from Turkey(2020) Kutuk, Meryem Ozlem; Tufan, Evren; Gokcen, Cem; Kilicaslan, Fethiye; Karadag, Mehmet; Mutluer, Tuba; Yektas, Cigdem; Coban, Nurdan; Kandemir, Hasan; Buber, Ahmet; Coskun, Seyma; Acikbas, Ufuk; Guler, Gulen; Topal, Zehra; Celik, Fatma; Altintas, Ebru; Giray, Asli; Aka, Yeliz; Kutuk, Ozgur; 0000-0002-2918-7871; 0000-0001-9854-7220; 0000-0003-2735-4805; 32563959; AAI-9626-2021; AAH-1671-2019; G-8832-2015Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by impairments in communication and social interaction as well as restricted interests and repetitive behaviors. The pathogenesis of ASD is not completely understood, but a growing body of research has demonstrated that the immune response may be a contributing factor in the etiology and/or ontogeny of ASD. The aim of this study was to determine the expression levels of IL-1 beta, IL-1 alpha, IL-4, IL-6, IL-17, TNF-alpha and TGF-beta in peripheral blood mononuclear cells of children with ASD and healthy controls in order to determine the contributions of cytokines to ASD. Within the study timeframe, 195 children with ASDs (80.5% male) and 162 controls (73.6% male) were enrolled. Most children with ASD had a comorbid disorder (n = 114, 58.5%), with the most common diagnoses as Intellectual Developmental Disorder (IDD, n = 64, 32.8%) and ADHD (n = 64, 32.8%). The majority of children with ASD had severe autistic symptoms as evaluated via Childhood Autism Rating Scale (CARS, n = 130, 64.6%). The mean CARS score in the ASD sample was 40.8 (S.D. = 7.6). The patients with ASD were found to have significantly higher levels of IL-6 (p < 0.001) and significantly lower levels of IL-17 (p < 0.05, all Bonferroni corrected). Treatment tended to affect IL-4 levels. Lastly, discriminant function analysis (DFA) revealed that a combination of IL-6, IL-17 and IL-1 alpha correctly classified 56.6% of cases. Despite extensive immunological evidence suggesting immune system aberrations, further research is required to clarify the relationship between immune profiles and ASD symptoms.Item RAB25 confers resistance to chemotherapy by altering mitochondrial apoptosis signaling in ovarian cancer cells(2020) Temel, Sehime Gulsun; Giray, Asli; Karaka, Bahriye; Gul, Ozgur; Kozanoglu, Ilknur; Celik, Husnu; Basaga, Huveyda; Acikbas, Ufuk; Sucularli, Ceren; Oztop, Sidika; Aka, Yeliz; Kutuk, Ozgur; 0000-0001-5653-6080; 0000-0001-9854-7220; 0000-0002-5268-1210; 32901335; AAJ-7911-2020; AAH-1671-2019; AAE-1241-2021Ovarian cancer remains one of the most frequent causes of cancer-related death in women. Many patients with ovarian cancer suffer from de novo or acquired resistance to chemotherapy. Here, we report that RAB25 suppresses chemotherapy-induced mitochondrial apoptosis signaling in ovarian cancer cell lines and primary ovarian cancer cells. RAB25 blocks chemotherapy-induced apoptosis upstream of mitochondrial outer membrane permeabilization by either increasing antiapoptotic BCL-2 proteins or decreasing proapoptotic BCL-2 proteins. In particular, BAX expression negatively correlates with RAB25 expression in ovarian cancer cells. BH3 profiling assays corroborated that RAB25 decreases mitochondrial cell death priming. Suppressing RAB25 by means of RNAi or RFP14 inhibitory hydrocarbon-stapled peptide sensitizes ovarian cancer cells to chemotherapy as well as RAB25-mediated proliferation, invasion and migration. Our data suggest that RAB25 is a potential therapeutic target for ovarian cancer.