Browsing by Author "Kutuk, Ozgur"

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Biphasic ROS production, p53 and BIK dictate the mode of cell death in response to DNA damage in colon cancer cells
(2017) Kutuk, Ozgur; Aytan, Nurgul; Karakas, Bahriye; Kurt, Asli Giray; Acikbas, Ufuk; Temel, Sehime Gulsun; Basaga, Huveyda; 0000-0001-9854-7220; 28796811; AAH-1671-2019
Necrosis, apoptosis and autophagic cell death are the main cell death pathways in multicellular organisms, all with distinct and overlapping cellular and biochemical features. DNA damage may trigger different types of cell death in cancer cells but the molecular events governing the mode of cell death remain elusive. Here we showed that increased BH3-only protein BIK levels promoted cisplatin-and UV-induced mitochondrial apoptosis and biphasic ROS production in HCT-116 wild-type cells. Nonetheless, early single peak of ROS formation along with lysosomal membrane permeabilization and cathepsin activation regulated cisplatin-and UV-induced necrosis in p53-null HCT-116 cells. Of note, necrotic cell death in p53-null HCT-116 cells did not depend on BIK, mitochondrial outer membrane permeabilization or caspase activation. These data demonstrate how cancer cells with different p53 background respond to DNA-damaging agents by integrating distinct cell signaling pathways dictating the mode of cell death.
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-8832-2015
Autism 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.
Cytotoxic and Apoptotic Effects of Novel Pyrrolo[2,3-d]Pyrimidine Derivatives Containing Urea Moieties on Cancer Cell Lines
(2018) Kilic-Kurt, Zuhal; Bakar-Ates, Filiz; Karakas, Bahriye; Kutuk, Ozgur; 0000-0003-2809-8946; 0000-0001-9616-4656; 0000-0001-9854-7220; 29866023; AAS-5399-2020; AAG-3843-2020; AFW-5486-2022; AAH-1671-2019
Background: Pyrrolo[2,3-d]pyrimidines have been recently reported to have anticancer activities through inhibition of different targets such as, Epidermal Growth Factor Receptor (EGFR) tyrosine kinase, Janus Kinase (JAK), mitotic checkpoint protein kinase (Mps1), carbonic anhydrase, MDM-2. On the other hand, aryl urea moieties which are found in some tyrosine kinase inhibitors such as Sorafenib and Linifanib have aroused recent attention as responsible for anticancer activities. The aims of this paper are to synthesize pyrrolo[2,3-d]pyrimidine derivatives containing urea moiety and evaluate their anti-cancer activity against human lung cancer cell line (A549), prostate cancer cell line (PC3), human colon cancer cell line (SW480) and human breast cancer cell line (MCF-7). Methods: A series of new pyrrolo[2,3-d]pyrimidines containing urea moieties have been synthesized as Scheme 1. In vitro cytotoxicity of target compounds were evaluated against, SW480, PC3, A549 and MCF-7 human cancer cell lines using a MTT assay. In order to evaluate the mechanism of cytotoxic activity of compounds 9e, 10a and 10b, having the best cytotoxic activity, Annexin V binding assay, cell cycle analysis and western blot analysis were performed. Results: Among the target compounds, 10a (IC50 = 0.19 mu M) was found to be the most potent derivative against PC3 cells. Compound 10b and 9e showed the strong cytotoxic activity against MCF-7 and A549 cells with IC50 value of 1.66 mu M and 4.55 mu M, respectively. Flow cytometry data suggest that the cytotoxic activity of the compounds on cancer cells might be mediated by apoptosis revealing a significant increase in the percentage of late apoptotic cells and causing a cell cycle arrest at different stages. Western blot analysis of apoptosis marker demonstrated that these compounds induce apoptosis through the intrinsic pathway. Conclusion: Compound 9e displayed the strongest cytotoxicity against A549 cancer cell line, and induced late apoptosis in A549, as confirmed by cell cycle arrest in G0/G1 phase. In addition, compound 9e reduced expression of the anti-apoptotic protein Bcl-2 and enhanced expression of the pro-apoptotic protein Bax, besides increased caspase-9 and caspase-3, as well as cleavage of PARP levels. These results suggest that compound 9e showed a cytotoxic effect in A549 cells through activation of the mitochondrial apoptotic pathway. Further studies will be undertaken in our laboratory to improve cytotoxic activity of compound 9e and to identify the biological targets of 9e which are responsible for anticancer activity.
Design, synthesis and in vitro apoptotic mechanism of novel pyrrolopyrimidine derivatives
(2019) Kilic-Kurt, Zuhal; Bakar-Ates, Filiz; Aka, Yeliz; Kutuk, Ozgur; 0000-0001-9854-7220; 30458413; AAH-1671-2019
In this work we described the synthesis and evaluation of cytotoxic and apoptotic activity of novel pyrrolopyrimidine derivatives against A549, PC3 and MCF-7 cells. Among the synthesized compounds, 6b, 8a, 9a and 7a, 8b displayed the significant cytotoxic activities against A549 and PC3 cells with IC50 value of 0.35, 1.48, 1.56 and 1.04, 1.89 mu M, respectively. It was found that A549 cells were more sensitive to synthesized compounds than PC3 and MCF-7 cells. In order to evaluate the mechanism of cytotoxic activity in A549, compounds 6b, 8a and 9a were selected for further studies. Annexin V binding assay and western blot analysis results revealed that 6b, 8a and 9a induced apoptosis in A549 cells by intrinsic apoptotic pathway through the activation proapoptotic proteins such as Bim, Bax, Bak, Puma and deactivation of anti-apoptotic proteins including Bcl-2, Mcl-1 and Bcl-XL accompanied by the activation of caspase-3, caspase-9 and cleavage of PARP. Also, compounds 6b, 8a and 9a triggered apoptosis in HCT116 wt cells via activation of caspase-3 and caspase-9, but not in HCT116 Bax/Bak KO cells, indicating resistance to 6b, 8a and 9a treatment.
Developmental delays and psychiatric diagnoses are elevated in offspring staying in prisons with their mothers
(2018) Kutuk, Meryem Ozlem; Altintas, Ebru; Tufan, Ali Evren; Guler, Gulen; Aslan, Betul; Aytan, Nurgul; Kutuk, Ozgur; 0000-0001-5207-6240; 0000-0001-9854-7220; 0000-0002-2918-7871; 0000-0003-2735-4805; 29382903; AAH-1846-2019; C-5074-2015; AAH-1671-2019; AAI-9626-2021; G-8832-2015
The aim of the study was to describe the sociodemographic and clinical features of the mothers and their offspring staying with them in prison. The study was planned as a cross-sectional, single-center study of mothers residing in Tarsus Closed Women's Prison of Turkish Ministry of Justice along with their 0 to 6 years old offspring. Mothers were evaluated via Structured Clinical Interview for DSM-IV Axis I Disorders. A psychologist blind to maternal evaluations applied the Denver Developmental Screening Test II (DII-DST). Children/mothers were also evaluated by a child and adolescent psychiatrist via K-SADS-PL. Twenty-four mothers with a mean age of 29.3 years were included. Most common diagnoses in mothers were nicotine abuse (n = 17, 70.8%), specific phobia (n = 8, 33.3%), alcohol abuse (n = 7, 29.2%) and substance abuse (n = 5, 20.8%). Twenty-six children (53.9% female) were living with their mothers in prison, and the mean age of those was 26.3 months. Results of the D-II-DST were abnormal in 33.3% of the children. Most common diagnoses in children were adjustment disorder (n = 7, 26.9%) separation anxiety disorder (n = 3, 11.5%) and conduct disorder (n = 2, 7.7%). A multi-center study is necessary to reach that neglected/under-served population and address the inter-generational transmission of abuse, neglect, and psychopathology.
Distinct Apoptotic Blocks Mediate Resistance to Panher Inhibitors in HER2+Breast Cancer Cells
(2018) Karakas, Bahriye; Ozmay, Yeliz; Basaga, Huveyda; Gul, Ozgur; Kutuk, Ozgur; https://orcid.org/0000-0001-9854-7220; 29733883; AAH-1671-2019
Despite the development of novel targeted therapies, de novo or acquired chemoresistance remains a significant factor for treatment failure in breast cancer therapeutics. Neratinib and dacomitinib are irreversible panHER inhibitors, which block their autophosphorylation and downstream signaling. Moreover, neratinib and dacomitinib have been shown to activate cell death in HER2-overexpressing cell lines. Here we showed that increased MCL1 and decreased BIM and PUMA mediated resistance to neratinib in ZR-75-30 and SKBR3 cells while increased BCL-XL and BCL-2 and decreased BIM and PUMA promoted neratinib resistance in BT474 cells. Cells were also cross-resistant to dacomitinib. BH3 profiles of HER2 + breast cancer cells efficiently predicted antiapoptotic protein dependence and development of resistance to panHER inhibitors. Reactivation of ERK1/2 was primarily responsible for acquired resistance in SKBR3 and ZR-75-30 cells. Adding specific ERK1/2 inhibitor SCH772984 to neratinib or dacomitinib led to increased apoptotic response in neratinib-resistant SKBR3 and ZR75-30 cells, but we did not detect a similar response in neratinib-resistant BT474 cells. Accordingly, suppression of BCL-2/BCL-XL by ABT-737 was required in addition to ERK1/2 inhibition for neratinib- or dacomitinib-induced apoptosis in neratinib-resistant BT474 cells. Our results showed that different mitochondrial apoptotic blocks mediated acquired panHER inhibitor resistance in HER2 + breast cancer cell lines as well as highlighted the potential of BH3 profiling assay in prediction of panHER inhibitor resistance in breast cancer cells.
Editorial: Cell Death and Targeted Cancer Therapies
(2022) Bagci-Onder, Tugba; Kutuk, Ozgur; Chonghaile, Triona Ni; Knippschild, Uwe; 000829492900001
Evaluating clonidine response in children and adolescents with attention-deficit/hyperactivity disorder
(2018) Kutuk, Meryem Ozlem; Guler, Gulen; Tufan, Ali Evren; Sungur, Mehmet Ali; Topal, Zehra; Kutuk, Ozgur
Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in childhood, which is generally treated with stimulant and non-stimulant medications. However, 10-30% of patients in clinical setting do not present with adequate response to initial stimulant treatment. Thereby, clonidine may be considered for those patients who have failed to respond to psychostimulant/atomoxetine monotherapy or as an augmentation for inadequate response/comorbidity. This observational study evaluated its effectiveness as a single drug in ADHD cases unresponsive to previous treatment trials. Seventeen ADHD cases that were non-responders to stimulant, non-stimulant and combination therapy for the primary symptoms of ADHD were included in the study. Four cases dropped out before follow up, leaving thirteen cases who were administered immediate release clonidine treatment alone with a mean dose of 0.2 +/- 0.05 mg/day at baseline. The trial lasted for 12 weeks, and treatment outcomes were evaluated by the Turgay DSM-IV Based Child and Adolescent Behavior Disorders Screening and Rating Scale (T-DSM-IV-S) and the Clinical Global Impressions-Severity (CGI-S) and Improvement (CGI-I) scales. Mean age of the sample was 12.5 years (SD = 3.0) and eleven of the subjects had another comorbid psychopathology. Only two cases were evaluated as "very much improved", while another patient was judged to be "minimally improved" after 12 weeks of clonidine treatment. Attrition during follow-up was associated with higher median scores on the hyperactivity and impulsivity subscales (Mann-Whitney U test, p = 0.02). According to the T-DSM-IV-S, CGI-S, and CGI-I scales, clonidine treatment by itself had minimal benefits in this sample of treatment of refractory cases with ADHD evaluated at the study center. Clonidine is not available in Turkey pharmaceutical marketing system and patients' access to drug is limited. Our results provide first data regarding the use of clonidine in Turkish ADHD patients.
An Exploratory, Single-Center Study of Factors Associated with Child Marriage Among Syrian Female Adolescents Residing in Turkey
(2022) Kutuk, Meryem Ozlem; Kilicaslan, Fethiye; Tufan, Ali Evren; Celik, Fatma; Gokcen, Cem; Bag, Harika Gozukara; Servi, Gulay; Karali, Mehtap; Bahsi, Gamze; Servi, Ceyhun; Alatli, Resat; Kandemir, Betul; Aytekin, Neslihan; Kutuk, Ozgur; https://orcid.org/0000-0001-9854-7220; AAH-1671-2019
This exploratory study aimed to evaluate factors related with child marriage compared to unmarried status in female adolescent residents in a refugee camp in Turkey. The rate of child marriage and developmental status of offspring from those marriages were reported. A research team evaluated married female youth and their offspring for psychopathologies according to DSM-5 criteria and ascertained lifetime traumatic events among mothers. We compared the traumatic experiences and psychopathologies of married females and controls. Post-traumatic stress disorder (PTSD) was the most common diagnosis in both groups and child brides reported greater cumulative traumatic experiences and elevated rates of PTSD. More than one-tenth (i.e., 15.1%) of offspring of child brides displayed developmental delays and 12.1% were diagnosed with global developmental delay.
Functional Outcome in Late Adolescence/Early Adulthood of Patients with Autism Spectrum Disorderresand Its Relationships with Parental Burnout and Depression: A Preliminary Multi-Center, Cross-Sectional Study
(2023) Kutuk, Meryem Ozlem; Soylemez, Tugba Eseroglu; Taner, Hande Ayraler; Altintas, Ebru; Kutuk, Ozgur; 37867841
The aim of this study is to determine the functioning of adults with autism spectrum disorders (ASDs) diagnosed in childhood and depression and burnout levels among their parents. A total of 261 adults with ASDs and their parents were recruited for the study. Both parents completed the Beck Depression and Maslach Burnout Inventories and reported the functioning of their adult offspring with ASDs. Only 5.4 % of our sample reported "good" or "very good" outcomes. The most common psychiatric comorbidities were intellectual disabilities and attention-deficit/ hyperactivity disorder. Maternal burnout and depression scores were significantly elevated compared to those of fathers. There is an undeniable urgent need for more research to identify the needs of adults and families suffering from ASD. Modifications for those with ASD may have to be made for support in workplaces, achieving driving licenses, using public transportation and attendance at tertiary education.
Hedgehog Signal Defect Leading to Familial Exudative Vitreoretinopathy-Like Disease and Gastrointestinal Malformation
(2022) Keskek, Nedime Sahinoglu; Akkoyun, Imren; Temiz, Abdulkerim; Kutuk, Ozgur; https://orcid.org/0000-0001-8544-103X; https://orcid.org/0000-0002-2860-7424; https://orcid.org/0000-0001-9854-7220; 35770050; T-4258-2017; AAK-7713-2021
Objectives: The aim of the study was to present a new generic association presenting with gastrointestinal tract malformations (GTMs) and familial exudative vitreoretinopathy (FEVR)-like disease and review the genetics of Hedgehog signaling. Materials and Methods: Three neonates were diagnosed with FEVR-like retinal vascular disease upon routine ophthalmological examination during hospitalization in the neonatal surgical intensive care unit for GTMs. Generic analysis of the neonates was performed. Results: Gestational age of the neonates was 39, 38, and 39 weeks and birth weights were 3,500, 3,600, and 3,300 grams, respectively. All six eyes of the three infants were treated by laser photocoagulation. Recurrence was not seen in any of the eyes. Genetical analysis of all the neonates diagnosed with FEVR-like disease revealed defects in the Hedgehog pathway. Conclusion: FEVR is a genetically well-defined retinal vascular disease. The current study is the first to show an association between FEVR-like retinal vascular disease and GTMs. This study demonstrates the importance of the Hedgehog pathway in retinal vascular and gut development.
Hiccup Due to Aripiprazole Plus Methylphenidate Treatment in an Adolescent with Attention Deficit and Hyperactivity Disorder and Conduct Disorder: A Case Report
(2017) Kutuk, Meryem Ozlem; Guler, Gulen; Tufan, Ali Evren; Kutuk, Ozgur; 0000-0002-2918-7871; 0000-0001-9854-7220; 29073754; AAI-9626-2021; AAH-1671-2019
Our case had hiccups arising in an adolescent with the attention deficit and hyperactivity disorder (ADHD) and conduct disorder (CD) after adding aripiprazole treatment to extended-release methylphenidate. Actually, antipsychotics are also used in the treatment of hiccups, but studies suggest that they can cause hiccups as well. Within 12 hours of taking 2.5 mg aripiprazole added to extended-release methylphenidate at a dose of 54 mg/day, 16-year-old boy began having hiccups in the morning, which lasted after 3-4 hours. As a result, aripiprazole was discontinued and methylphenidate was continued alone because we could not convince the patient to use another additional drug due to this side effect. Subsequently, when his behavior got worsened day by day, his mother administered aripiprazole alone again at the dose of 2.5 mg/day at the weekend and continued treatment because hiccup did not occur again. But when it was administered with methylphenidate on Monday, hiccup started again next morning and lasted one hour at this time. In conclusion, we concluded that concurrent use of methylphenidate and aripiprazole in this adolescent led to hiccups.
High Depression Symptoms and Burnout Levels Among Parents of Children with Autism Spectrum Disorders: A Multi-Center, Cross-Sectional, Case-Control Study (Jan, 10.1007/s10803-021-04874-4, 2021)
(2021) Kutuk, Meryem Ozlem; Tufan, Ali Evren; Kilicaslan, Fethiye; Guler, Gulen; Celik, Fatma; Altintas, Ebru; Gokcen, Cem; Karadag, Mehmet; Yektas, Cigdem; Mutluer, Tuba; Kandemir, Hasan; Buber, Ahmet; Topal, Zehra; Acikbas, Ufuk; Giray, Asli; Kutuk, Ozgur; 0000-0002-2918-7871; 0000-0001-9854-7220; 33591437; AAI-9626-2021
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; 34171479
Antiapoptotic 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.
Migraine and Associated Comorbidities are Three Times More Frequent in Children With ADHD and Their Mothers
(2018) Kutuk, Meryem Ozlem; Tufan, Ali Evren; Guler, Gulen; Yalin, Osman Ozgur; Altintas, Ebru; Bag, Harika Gozukara; Uluduz, Derya; Toros, Fevziye; Aytan, Nurgul; Kutuk, Ozgur; Ozge, Aynur; https://orcid.org/0000-0002-2918-7871; https://orcid.org/0000-0001-5207-6240; https://orcid.org/0000-0003-2735-4805; https://orcid.org/0000-0001-9854-7220; 29921473; AAI-9626-2021; C-5074-2015; G-8832-2015; AAH-1671-2019
Objective: Attention deficit and hyperactivity disorder (ADHD) is a neuro-developmental disorder related to internalizing and externalizing disorders as well as somatic complaints and disorders. This study was conducted to evaluate the prevalence of headache subtypes, epilepsy, atopic disorders, motion sickness and recurrent abdominal pain among children and adolescents with ADHD and their parents. Methods: In a multi-center, cross-sectional, familial association study using case-control design, treatment na ve children and adolescents between 6 and 18 years of age diagnosed with ADHD according to the DSM-5 criteria as well as age- and gender matched healthy controls and their parents were evaluated by a neurologist and analyzed accordingly. Results: 117 children and adolescents with ADHD and 111 controls were included. Headache disorder diagnosis was common for both patients and healthy controls (59.0% vs. 37.8%), with a significantly elevated rate in the ADHD group (p = 0.002). Migraine was found in 26.0% of ADHD patients and 9.9% of healthy controls. Tension headache was found in 32.4% of ADHD patients and 27.9% of healthy controls. Headache diagnosis was also found to be significantly more common in mothers of children with ADHD than control group mothers (90.5% vs. 36.6%, p < 0.001). Conclusion: Headache diagnoses and specifically migraines were significantly more common among children with ADHD and their mothers, while recurrent abdominal pain was elevated in both parents and ADHD patients. Migraine is an important part of ADHD comorbidity, not only for children but also for mothers. Motion sickness may be reduced among families of ADHD probands. (C) 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Mitochondrial estrogen receptors alter mitochondrial priming and response to endocrine therapy in breast cancer cells
(2021) Karakas, Bahriye; Aka, Yeliz; Giray, Asli; Temel, Sehime Gulsum; Acikbas, Ufuk; Basaga, Huveyda; Gul, Ozgur; Kutuk, Ozgur; 34294688
Breast cancer is the most common cancer with a high rate of mortality and morbidity among women worldwide. Estrogen receptor status is an important prognostic factor and endocrine therapy is the choice of first-line treatment in ER-positive breast cancer. However, most tumors develop resistance to endocrine therapy. Here we demonstrate that BH3 profiling technology, in particular, dynamic BH3 profiling can predict the response to endocrine therapy agents as well as the development of acquired resistance in breast cancer cells independent of estrogen receptor status. Immunofluorescence analysis and subcellular fractionation experiments revealed distinct ER-alpha and ER-beta subcellular localization patterns in breast cancer cells, including mitochondrial localization of both receptor subtypes. shRNA-mediated depletion of ER-beta in breast cancer cells led to resistance to endocrine therapy agents and selective reconstitution of ER-beta in mitochondria restored sensitivity. Notably, mitochondria-targeted ER-alpha did not restore sensitivity, even conferred further resistance to endocrine therapy agents. In addition, expressing mitochondria-targeted ER-beta in breast cancer cells resulted in decreased mitochondrial respiration alongside increased total ROS and mitochondrial superoxide production. Furthermore, our data demonstrated that mitochondrial ER-beta can be successfully targeted by the selective ER-beta agonist Erteberel. Thus, our findings provide novel findings on mitochondrial estrogen signaling in breast cancer cells and suggest the implementation of the dynamic BH3 technique as a tool to predict acquired endocrine therapy resistance.
A Novel Homozygous Nonsense Mutation in The Calpastatin (CAST) Gene Associated with Peeling Skin Phenotype in A Child
(2018) Saricaoglu, Hayriye; Temel, Sehime; Zorlu, Ozge; Turkgenc, Burcu; Kutuk, Ozgur; Karakas, Bahriye; Kiran, Ummuhan; Erguner, Bekir; Yakicier, Cengiz; https://orcid.org/0000-0001-9854-7220; AAH-1671-2019
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-9626-2021
Immune 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.
Novel pyrrolopyrimidine derivatives induce p53-independent apoptosis via the mitochondrial pathway in colon cancer cells
(2020) Kilic-Kurt, Zuhal; Aka, Yeliz; Kutuk, Ozgur; 0000-0001-9854-7220; 32866467; AAH-1671-2019
A series of novel pyrrolopyrimidine urea derivatives were synthesized and evaluated for their anticancer activity against colon cancer cell lines. Compounds showed the remarkable cytotoxic activity on HCT-116 wt cell line. The most potent compound 4c (IC50 = 0.14 mu M) induced apoptosis in HCT-116 wt and HCT-116 p53-/- cell lines. Otherwise, treatment of HCT-116 BAX-/-BAK-/- cells with compound 4c didn't lead to activation of apoptosis, suggesting that compound 4c induces apoptotic cell death by activating BAX/BAK-dependent pathway. Moreover, while the compound 4c increase the activation of caspase-3 and caspase-9 levels in HCT116 wt and HCT-116 p53-/- cells, caspase-3 or caspase-9 activation was not observed in HCT-116 BAX-/-BAK-/- cells. In addition, compound 4c induced mitochondrial apoptosis in cells grown as oncospheroids, which better mimic the in vivo milieu of tumors. 4c treatment also activated JNK along with inhibition of prosurvival kinases such as Akt and ERK 1/2 in HCT-116 wt and HCT-116 p53 -/- cells as well as in HCT-116 BAX-/-BAK-/- cells. Notably, our results indicated that compound 4c induced mitochondrial apoptosis through activation p53-independent apoptotic signaling pathways.
Phosphorylation switches Bax from promoting to inhibiting apoptosis thereby increasing drug resistance
(2018) Kutuk, Ozgur; Kale, Justin; Brito, Glauber Costa; Andrews, Talluhan S.; Leber, Brian; Letai, Anthony; Andrews, David W.; 0000-0001-9854-7220; AAH-1671-2019
Akt is a pro-survival kinase frequently activated in human cancers and is associated with more aggressive tumors that resist therapy. Here, we connect Akt pathway activation to reduced sensitivity to chemotherapy via Akt phosphorylation of Bax at residue S184, one of the pro-apoptotic Bcl-2 family proteins required for cells to undergo apoptosis. We show that phosphorylation by Akt converts the pro-apoptotic protein Bax into an anti-apoptotic protein. Mechanistically, we show that phosphorylation (i) enables Bax binding to pro-apoptotic BH3 proteins in solution, and (ii) prevents Bax inserting into mitochondria. Together, these alterations promote resistance to apoptotic stimuli by sequestering pro-apoptotic activator BH3 proteins. Bax phosphorylation correlates with cellular resistance to BH3 mimetics in primary ovarian cancer cells. Further, analysis of the TCGA database reveals that 98% of cancer patients with increased BAX levels also have an upregulated Akt pathway, compared to 47% of patients with unchanged or decreased BAX levels. These results suggest that in patients, increased phosphorylated anti-apoptotic Bax promotes resistance of cancer cells to inherent and drug-induced apoptosis.