PubMed Açık Erişimli Yayınlar
Permanent URI for this collectionhttps://hdl.handle.net/11727/10763
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Item Editorial: Cell Death and Targeted Cancer Therapies(2022) Bagci-Onder, Tugba; Kutuk, Ozgur; Chonghaile, Triona Ni; Knippschild, Uwe; 000829492900001Item 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-7713-2021Objectives: 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.Item 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; 34294688Breast 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.Item 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-1671-2019In 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.Item 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-1671-2019Necrosis, 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.Item 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-1671-2019Our 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.Item 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-8832-2015The 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.Item 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-1671-2019Akt 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.