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- YayınSadece MetadataAssessment of Interleukin-1 Gene Cluster Polymorphisms in Lone Atrial Fibrillation: New Insight into the Role of Inflammation in Atrial Fibrillation(Wiley-Blackwell, 111 River St, Hoboken 07030-5774, Nj USA, 2013-10) Çoker Gürkan, Ajda; Güngör, Barış; Ekmekçi, Ahmet; Arman, Ahmet; Özcan, Kazım S.; Üçer, Ekrem; Çalık, Nazmi; Yılmaz, Hale; Tezel, Tuna; Bolca, Osman; 125860; 173248BackgroundSystemic inflammation is accepted as one of the pathophysiological mechanisms of atrial fibrillation (AF). The role of inflammation has been shown previously. Interleukin (IL) system is the main modulator of the inflammatory responses and genetic polymorphisms of IL-1 cluster genes are associated with increased risk for inflammatory diseases. ObjectivesTo investigate the association between polymorphisms of IL-1 cluster genes and lone AF. Subjects and MethodsDNA samples were collected from 70 proven lone AF patients and 70 healthy subjects. Genomic DNA was typed for the variable number of the tandem repeat (VNTR) IL-1 receptor antagonist (RN) gene polymorphism, IL-1B -511 C > T(rs16944) promoter polymorphism, and +3953 C > T(rs1143634) polymorphism in exon 5 by polymerase chain reaction. ResultsIn lone AF group the frequency of IL-1RN2/2 and IL-1RN1/2 genotypes were higher than in the control group (7.2% vs 4.3% and 48.5% vs 22.8%, respectively; (2) = 14.1; P = 0.028). The frequency of allele 2 was significantly higher in the lone AF group (32.1% vs 15.7%; (2) = 10.7; P = 0.005). Allele and genotype distribution of IL-1B -511 C > T and +3953 C > T polymorphisms were not statistically different between the groups. C-reactive protein (CRP) levels were higher in lone AF patients compared to the control group (median = 1.25, interquartile range [IQR] = 0.85 vs median = 1.08, IQR 0.46 mg/L, respectively; P = 0.02). In multivariate regression analysis, presence of allele 2 of IL-1 VNTR polymorphism and elevated plasma high-sensitive-CRP levels were the independent predictors of lone AF. ConclusionPresence of allele 2 of VNTR polymorphism of IL-1RN gene may cause increased risk for lone AF probably due to the inadequate limitation of inflammatory reactions.
- YayınSadece MetadataAssociation between IL-1RN VNTR, IL-1 beta -511 and IL-6 (-174, -572, -597) Gene Polymorphisms and Urolithiasis(Karger, Allschwilerstrasse 10, Ch-4009 Basel, Switzerland, 2013) Çoker Gürkan, Ajda; Arısan, Elif Damla; Palavan Unsal, Narçin; Arısan, Serdar; Sonmez, Nurettin Cem; 125860; 113920; 6125Urolithiasis is a common multifactorial urological disorder that is characterized by stone formation. Interleukin (IL)-1 and IL-6 are pro-inflammatory cytokines that might be linked with urolithiasis. The single nucleotide polymorphisms within the IL-1 and IL-6 cytokine genes altered the cytokine expression levels. Our aim was to investigate the potential of IL-1 beta (-511 C>T), IL-6 (-174 G>C, 572 G>C, 597 G>A) and IL-1 RN VNTR gene polymorphisms to be a genetic marker for urinary stone disease. The polymorphisms studied in the promoter regions of IL-1 beta and IL-6 genes did not reveal a strong association with urolithiasis when compared to the control group (p = 0.293, 0.871, 0.921, 0.536, respectively). However, a significant difference was observed between control and patient groups for IL-1 RN VNTR gene polymorphism (chi(2) = 6.131, d.f. = 2, p = 0.047). Our data provide evidence that IL-1RN VNTR gene polymorphism may be involved in the pathogenesis of urinary stone formation, contributing to genetic susceptibility for urolithiasis. (C) 2013 S. Karger AG, Basel
- YayınAçık ErişimAutocrine Growth Hormone-Triggered Curcumin Resistance Abolished by NF-κB Signaling Pathway Dependent on Inflammatory Cytokines and Active Polyamine Catabolic Machinery in MCF-7, MDA-MB-453 and MDA-MB-231 Breast Cancer Cells(2017) Çoker Gürkan, Ajda; Çelik, Merve; Uğur, Merve; Arısan, Elif Damla; Obakan Yerlikaya, Pınar; Ünsal, Zeynep Narçin; 125860; 113920; 156421; 6125Autocrine Growth Hormone (GH) induces cell growth, proliferation metastasis in breast cancer. Curcumin is a promising therapeutic agent in cancer through affecting different molecular targets. Our aim was to demonstrate the molecular machinery of curcumin-mediated apoptosis in autocrine GH + MCF-7, MDA-MB-453 and MDA-MB-231 breast cancer cells (BCCs). Stable GH expressing BCCs were generated by GH gene insert PC3.1 plasmid transfection and Neomycin selection. Although GH + cells are resistant to curcumin treatment, dose-dependent drug exposure decreased cell viability, inhibited colony formation, invasion-metastasis via suppressing GH expression in each BCCs. Anti-hormonal concentration of curcumin (20 µM for MCF-7, MDA-MB-453 and 25 µM for MDA-MB-231) inhibited NF-κB p65 (Ser 536) phosphorylation and decreased DNA binding activity of NF-κB p65 in autocrine GH expressing BCCs. In addition, autocrine GH-mediated IL-1α, IL-6, IL-1β pro-inflammatory cytokine expressions downregulated by curcumin treatment. Moreover, curcumin overcome autocrine GH triggered drug resistant and induced caspase-mediated apoptotic cell death through activating Polyamine (PA) catabolic pathway enzymes which led to generation of toxic by-products such as H2O2 in MCF-7, MDA-MB-453 and MDA-MB-231 GH + BCCs. In conclusion, curcumin could overcome GH-mediated resistant phenotype via modulating NF-κB-mediated inflammatory cytokine expression and PA catabolic machinery activation in breast cancer cells.
- YayınAmbargoluBag-1L is a Stress-withstand Molecule Prevents the Downregulation of Mcl-1 and c-Raf Under Control of Heat Shock Proteins in Cisplatin Treated HeLa Cervix Cancer Cells(Asian Pacific Organization Cancer Prevention, Apjcp Head Office, Korean Natl Cancer Center, 323 Ilan -Ro, Ilsandong-Gu, Goyang-Si, Gyeonggi-Do, 410-769, South Korea, 2014) Özfiliz Kılbaş, Pelin; Arısan, Elif Damla; Çoker Gürkan, Ajda; Obakan, Pınar; Eralp, Tuğçe Nur; Dinler Doğanay, Gizem; Palavan Unsal, Narçin; 195744; 113920; 125860; 156421; 272026; 152975; 6125Background: Cisplatin, a DNA damaging agent, induces apoptosis through increasing DNA fragmentation. However, identification of intrinsic resistance molecules against Cisplatin is vital to estimate the success of therapy. Bag-1 (Bcl-2-associated anthanogene) is one anti-apoptotic protein involved in drug resistance impacting on therapeutic efficiency. Elevated levels of this protein are related with increase cell proliferation rates, motility and also cancer development. For this reason, we aimed to understand the role of Bag-1 expression in Cisplatin-induced apoptosis in HeLa cervix cancer cells. Cisplatin decreased cell viability in time-and dose-dependent manner in wt and Bag-1L+HeLa cells. Although, 10 mu M Cisplatin treatment induced cell death within 24h by activating caspases in wt cells, Bag-1L stable transfection protected cells against Cisplatin treatment. To assess the potential protective role of Bag-1, we first checked the expression profile of interacting anti-apoptotic partners of Bag-1. We found that forced Bag-1L expression prevented Cisplatin-induced apoptosis through acting on Mcl-1 expression, which was reduced after Cisplatin treatment in wt HeLa cells. This mechanism was also supported by the regulation of heat shock protein (Hsp) family members, Hsp90 and Hsp40, which were involved in the regulation Bag-1 interactome including several anti-apoptotic Bcl-2 family members and c-Raf.
- YayınAmbargoluBag-1L mediated chemoresistance mechanism through preventing downregulation of Mcl-1 and c-Raf by heat shock proteins in HeLa cells(2014-11) Eralp, Tuğçe Nur; Arısan, Elif Damla; Özfiliz, Pelin; Obakan Yerlikaya, Pınar; Çoker Gürkan, Ajda; Dinler Doğanay, Gizem; Ünsal, Zeynep Narçin; 272026; 113920; 195744; 156421; 125860; 152975; 6125Background: Cisplatin, a DNA damaging agent, induces apoptosis through increasing DNA fragmentation. However, identification of intrinsic resistance molecules against Cisplatin is vital to estimate the success of therapy. Bag-1 (Bcl-2-associated anthanogene) is one anti-apoptotic protein involved in drug resistance impacting on therapeutic efficiency. Elevated levels of this protein are related with increase cell proliferation rates, motility and also cancer development. For this reason, we aimed to understand the role of Bag-1 expression in Cisplatininduced apoptosis in HeLa cervix cancer cells. Cisplatin decreased cell viability in time- and dose-dependent manner in wt and Bag-1L+HeLa cells. Although, 10μM Cisplatin treatment induced cell death within 24h by activating caspases in wt cells, Bag-1L stable transfection protected cells against Cisplatin treatment. To assess the potential protective role of Bag-1, we first checked the expression profile of interacting anti-apoptotic partners of Bag-1. We found that forced Bag-1L expression prevented Cisplatin-induced apoptosis through acting on Mcl-1 expression, which was reduced after Cisplatin treatment in wt HeLa cells. This mechanism was also supported by the regulation of heat shock protein (Hsp) family members, Hsp90 and Hsp40, which were involved in the regulation Bag-1 interactome including several anti-apoptotic Bcl-2 family members and c-Raf.
- YayınSadece MetadataCalreticulin is a fine tuning molecule in epibrassinolide-induced apoptosis through activating endoplasmic reticulum stress in colon cancer cells(Wiley, 111 River St, Hoboken 07030-5774, NJ USA, 2017-06) Obakan Yerlikaya, Pınar; Arısan, Elif Damla; Çoker Gürkan, Ajda; Adacan, Kaan; Özbey, Utku; Somuncu, Berna; Baran, Didem; Ünsal Palavan, Zeynep Narçın; 156421; 113920; 125860; 6125Epibrassinolide (EBR), a member of brassinostreoids plant hormones with cell proliferation promoting role in plants, is a natural polyhydroxysteroid with structural similarity to steroid hormones of vertebrates. EBR has antiproliferative and apoptosis-inducing effect in various cancer cells. Although EBR has been shown to affect survival and mitochondria-mediated apoptosis pathways in a p53-independent manner, the exact molecular targets of EBR are still under investigation. Our recent SILAC (Stable Isotope Labeling by Amino Acids in Cell Culture) data showed that the most significantly altered protein after EBR treatment was calreticulin (CALR). CALR, a chaperone localized in endoplasmic reticulum (ER) lumen, plays role in protein folding and buffering Ca2+ ions. The alteration of CALR may cause ER stress and unfolded protein response correspondingly the induction of apoptosis. Unfolded proteins are conducted to 26S proteasomal degradation following ubiquitination. Our study revealed that EBR treatment caused ER stress and UPR by altering CALR expression causing caspase-dependent apoptosis in HCT 116, HT29, DLD-1, and SW480 colon cancer cells. Furthermore, 48 h EBR treatment did not caused UPR in Fetal Human Colon cells (FHC) and Mouse Embryonic Fibroblast cells (MEF). In addition our findings showed that HCT 116 colon cancer cells lacking Bax and Puma expression still undergo UPR and related apoptosis. CALR silencing and rapamycin co-treatment prevented EBR-induced UPR and apoptosis, whereas 26S proteasome inhibition further increased the effect of EBR in colon cancer cells. All these findings showed that EBR is an ER stress and apoptotic inducer in colon cancer cells without affecting nonmalignant cells.
- YayınAmbargoluCathepsin K analysis in a pycnodysostosis cohort: demographic, genotypic and phenotypic features(Biomed Central Ltd, 236 Grays Inn Rd, Floor 6, London Wc1X 8Hl, England, 2014-04-26) Arman, Ahmet; Bereket, Abdullah; Çoker Gürkan, Ajda; Şimşek Kiper, Pelin Özlem; Güran, Tülay; Özkan, Behzat; Atay, Zeynep; Akçay, Teoman; Haliloğlu, Belma; Boduroğlu, Koray; Alanay, Yasemin; Turan, Serap; 173248; 9240; 125860; 169245; 183446; 171694; 201621; 218579; 206057; 28175; 125850Background: To characterize cathepsin K (CTSK) mutations in a group of patients with pycnodysostosis, who presented with either short stature or atypical fractures to pediatric endocrinology or dysmorphic features to pediatric genetics clinics. Methods: Seven exons and exon/intron boundaries of CTSK gene for the children and their families were amplified with PCR and sequenced. Sixteen patients from 14 families with pycnodysostosis, presenting with typical dysmorphic features, short stature, frequent fractures and osteosclerosis, were included in the study. Results: We identified five missense mutations (M1I, I249T, L7P, D80Y and D169N), one nonsense mutation (R312X) and one 301 bp insertion in intron 7, which is revealed as Alu sequence; among them, only L7P and I249 were described previously. The mutations were homozygous in all cases, and the families mostly originated from the region where consanguineous marriage rate is the highest. Patients with M1I mutation had fractures, at younger ages than the other pycnodysostosis cases in our cohort which were most probably related to the severity of mutation, since M1I initiates the translation, and mutation might lead to the complete absence of the protein. The typical finding of pycnodysostosis, acroosteolysis, could not be detected in two patients, although other patients carrying the same mutations had acroosteolysis. Additionally, none of the previously described hot spot mutations were seen in our cohort; indeed, L7P and R312X were the most frequently detected mutations. Conclusions: We described a large cohort of pycnodysostosis patients with genetic and phenotypic features, and, first Alu sequence insertion in pycnodysostosis.
- YayınSadece MetadataCDK Inhibitors Induce Mitochondria-mediated Apoptosis Through the Activation of Polyamine Catabolic Pathway in LNCaP, DU145 and PC3 Prostate Cancer Cells(Bentham Science Publ Ltd, Executive Ste Y-2, Po Box 7917, Saif Zone, 1200 Br Sharjah, U Arab Emirates, 2014-01) Arısan, Elif Damla; Obakan, Pınar; Çoker Gürkan, Ajda; Calcabrini, Annarica; Agostinelli, Enzo; Palavan Unsal, Narçin; 113920; 156421; 125860; 6125Androgen signaling is critical in prostate cancer development and progression. The co-existence of hormone responsive and irresponsive cells due to functional androgen receptor (AR) in prostate gland is the major obstacle in prostate cancer therapy models. Targeting aberrant cell cycle by novel cell cycle blocking agents is a promising strategy to treat various types of malignancies. Purvalanol and roscovitine are cyclin dependent kinase (CDK) inhibitors able to activate apoptotic cell death by inducing cell cycle arrest at G1/S and G2/M phases in cancer cells. Polyamines are unique cationic amine derivatives involved in the regulation of cell proliferation. Although the elevated intracellular level of polyamines (putrescine, spermidine and spermine) is typical for prostate gland, abnormal regulation of polyamine metabolism might result in rapid cell proliferation and, thus in prostate cancer progression. Therefore, treatment with drug-induced depletion of intracellular polyamine levels through the activated polyamine catabolism is critical to achieve successful strategies for prostate cancer. In this study we aimed to investigate the apoptotic efficiency of CDK inhibitors in three prostate cancer cell lines (LNCaP, DU145 and PC3), showing different AR expression profile. We found that both purvalanol and roscovitine were able to induce apoptosis at moderate cytotoxic concentrations by decreasing mitochondria membrane potential. The apoptotic effect of both CDK inhibitors was due to activation of caspases by modulating Bcl-2 family members. The efficiency of drugs was quite similar on the three prostate cell lines used in this study. However, DU145 cells were found the least sensitive against CDK inhibitors while purvalanol was more potent than roscovitine. Similarly to classical chemotherapeutic agents, both drugs could up-regulate polyamine catabolic enzymes (SSAT, SMO and PAO) in cell type dependent manner. Transient silencing of SSAT and/or inhibition of PAO/SMO with MDL72527 prevented CDK inhibitors-induced apoptotic cell death in DU145 and PC3 cells. Although roscovitine was less effective in DU145 cells, pre-treatment with alpha-difluoromethylornithine (DFMO), an inhibitor of ODC, enhanced the roscovitine-induced apoptotic cell death through the cleavage of caspase-9 and caspase-3. Therefore, we conclude that polyamine catabolism might have essential role in the cellular responses against CDK inhibitors in different androgen-responsive or irresponsive prostate cancer cells.
- YayınAmbargoluCDK inhibitors-induced SSAT expression requires NF kappa B and PPAR gamma in MCF-7 breast cancer cells(TUBİTAK Scientific & Technical Research Council Turkey, Ataturk Bulvarı No 221, Kavaklıdere, Ankara, 00000, Turkey, 2015) Obakan Yerlikaya, Pınar; Yıldırım, Şeyma; Öztürk, Mert Burak; Berrak, Özge; Çoker Gürkan, Ajda; Arısan, Elif Damla; Ünsal Palavan, Zeynep Narçın; 156421; 125860; 113920; 6125The cyclin-dependent kinase (CDK) inhibitors purvalanol and roscovitine are therapeutic agents that control cell proliferation through regulating cell-cycle machinery. They also affect polyamine (PA) metabolism, which is activated in malignant tissues. Therefore, PA catabolism became a remarkable target in cancer therapies. Induction of the PA catabolic enzyme spermidine/spermine N-1-acetyltransferase (SSAT) is under the control of transcription factors such as NF kappa B and PPAR gamma. The purpose of this study was to investigate the therapeutic potential of CDK inhibitors in combination with PAs in MCF-7 breast cancer cells. In order to understand the involvement of PA catabolic enzyme SSAT in this process we also checked its transcriptional regulation in the presence of CDK inhibitors. MCF-7 cells were exposed to CDK inhibitors in the absence or presence of Spd and Spm. Cell viability loss was evaluated by MTT assay. Apoptosis was determined by annexin-V/PI staining using FACS flow. The SSAT transcription level was measured by qRT-PCR. Intracellular PA pool was determined by HPLC. Protein expressions were assessed by western blotting. We found that CDK inhibitors decreased cell viability in a time-dependent manner and induced apoptosis. Co-treatment of Spd or Spm with CDK inhibitors prevented the apoptotic potential of both drugs. Purvalanol increased SSAT expression levels in a time-dependent manner. Although the induction of SSAT by purvalanol resulted in the activation of NF kappa B at early time points, induction was accomplished by PPAR gamma as a late response after purvalanol treatment. We concluded that both transcriptional control mechanisms could be responsible for SSAT regulation in a time-dependent manner.
- YayınAçık ErişimCelastrol Modulates Lipid Synthesis via PI3K/Akt/mTOR Signaling Axis to finalize Cell Death Response in Prostate Cancer Cells(2017) Arısan, Elif Damla; Rencüzoğulları, Özge; Çoker Gürkan, Ajda; Obakan Yerlikaya, Pınar; Ünsal, Zeynep Narçin; 113920; 222563; 125860; 156421; 6125FASN is key enzyme during lipid biogenesis is associated with prostate cancer. In this study, we aim to investigate the potential role of celastrol, root extracts of Tripterygium wilfordii on modulation of lipid biosynthesis-associated PI3K/Akt signaling. To determine the effect of celastrol on cell viability, prostate cancer cells were exposed with celastrol in dose dependent manner. AR (+) LNCaP and AR (−) DU145 and PC3 cell viability were inhibited by celastrol with IC50 in the range of 0.05–1 µM. To address the role of celastrol on cell death mechanism, celastrol-treated prostate cancer cells were evaluated with immunoblotting and flow cytometric analysis. Celastrol significantly upregulated PARP and caspase 9 cleavage also increased sub-G1 population. Celastrol also inhibited cell migration and invasion. These effects were associated with decreased PI3K/Akt signaling axis and downregulation of epithelial mesenchymal transition in prostate cancer cells. Likewise, lipid biosynthesis was downregulated with celastrol, however inhibition of PI3K/Akt signaling axis via LY294002 further decrease the cell migration and proliferation rate in prostate cancer cells. Our data suggest that, celastrol suppressed cell proliferation via inhibition of lipid biosynthesis through downregulation of PI3K/Akt signal axis. Targeting lipid metabolism-related enzymes in prostate cancer may offer new avenues for therapeutic approaches.
- YayınSadece MetadataCombined Treatment of Roscovitine and DFMO Induced Caspase Dependent Apoptosis in MCF-7 cells. 2nd(2010) Obakan Yerlikaya, Pınar; Arısan, Elif Damla; Ünsal, Zeynep Narçin; Çoker Gürkan, Ajda; 156421; 113920; 6125; 125860
- YayınAçık ErişimThe Comparison of Differentially Expressed microRNAs in Bag-1 Deficient and Wild Type MCF-7 Breast Cancer Cells by Small RNA Sequencing(TUBITAK Scientific & Technical Research Council Turkey, 2022) KILBAŞ, PELİN ÖZFİLİZ; Alkurt, Gizem; Obakan Yerlikaya, Pınar; Çoker Gürkan, Ajda; DİNLER DOĞANAY, GİZEM; Arısan, Elif DamlaThe multifunctional BAG-1 (Bcl-2 athanogene-1) protein promotes breast cancer survival through direct or indirect interaction partners. The number of the interacting partners determines its cellular role in different conditions. As well as interaction partner variability, the amount of BAG-1 protein in the cells could cause dramatic alterations. According to previous studies, while the transient silencing of Bag-1 enhanced drug-induced apoptosis, deletion of BAG-1 could induce stemness properties and Akt-mediated actin remodeling in MCF-7 breast cancer cells. Considering the heterogeneity of breast cancer and the variability of BAG-1-mediated cell response, it has become essential to determine microRNA (miRNA) functions in breast cancer depending on Bag-1 expression level. This study aims to compare microRNA expression levels in wt and Bag-1 knockout (KO) MCF-7 breast cancer cells. hsa-miR-429 was selected as a potential miRNA in BAG-1KO MCF-7 cells because of the downregulation both in bioinformatics and validation qRT-PCR assay. According to predicted mRNA targets and functional enrichment analysis the ten hub proteins that are phosphatidylinositol4,5-biphosphate 3-kinase catalytic subunit alpha (PIK3CA), kinase insert domain receptor (KDR), GRB2 associated binding protein 1 (GAB1), Rac family small GTPase1 (RAC1), vascular endothelial growth factor A (VEGFA), Cbl proto-oncogene (CBL), syndecan 2 (SDC2), phospholipase C gamma 1 (PLCG1), E1A binding protein p300 (EP300), and CRK like proto-oncogene, adaptor protein (CRKL) were identified as targets of hsa-miR-429. The functional enrichment analysis showed that the most significant proteins were enriched in PI3K/Akt, focal adhesion, cytoskeleton regulation, proteoglycans in cancer, and Ras signaling pathways. It was determined that hsa-miR-429 targeted these pathways in Bag-1 deficient conditions and could be used as a potential therapeutic target in future studies.
- YayınSadece MetadataCox-2 inhibitor ibuprofen induced apoptosis via altering different signalling routes in HT-29 and DLD-1 colon cancer cells(2015) Yalçın, Gizem Damla; Arısan, Elif Damla; Çoker Gürkan, Ajda; Obakan Yerlikaya, Pınar; Ünsal, Zeynep Narçin; 113920; 125860; 156421; 6125
- YayınSadece MetadataCurcumin induced-apoptotic cell death in GH overexpressed MDA-MB-231 breast cancer in time dependent manner(2015) Çelik, Merve; Çoker Gürkan, Ajda; Arısan, Elif Damla; Obakan Yerlikaya, Pınar; Ünsal, Zeynep Narçin; 125860; 113920; 156421; 6125
- YayınSadece MetadataCurcumin induced-apoptotic cell death in GH overexpressed MDA-MB-231 breast cancer in time dependent manner(Wiley-Blackwell, 111 River St, Hoboken 07030-5774, NJ USA, 2015-07) Çelik, Merve; Çoker Gürkan, Ajda; Arısan, Elif Damla; Yerlikaya, Pınar Obakan; Palavan Ünsal, Zeynep Narçın; 125860; 113920; 156421; 6125
- YayınSadece MetadataCurcumin inhibits autocrine growth hormone-mediated invasion and metastasis by targeting NF-kappa B signaling and polyamine metabolism in breast cancer cells(2018-08) Çoker Gürkan, Ajda; Çelik, Merve; Uğur, Merve; Arısan, Elif Damla; Obakan Yerlikaya, Pınar; Durdu, Zeynep Begüm; Ünsal Palavan, Zeynep Narçın; 125860; 156421; 113920; 6125Curcumin is assumed to be a plant-derived therapeutic drug that triggers apoptotic cell death in vitro and in vivo by affecting different molecular targets such as NF-kappa B. Phase I/II trial of curcumin alone or with chemotherapeutic drugs has been accomplished in pancreatic, colon, prostate and breast cancer cases. Recently, autocrine growth hormone (GH) signaling-induced cell growth, metastasis and drug resistance have been demonstrated in breast cancer. In this study, our aim was to investigate the potential therapeutic effect of curcumin by evaluating the molecular machinery of curcumin-triggered apoptotic cell death via focusing on NF-kappa B signaling and polyamine (PA) metabolism in autocrine GH-expressing MCF-7, MDA-MB-453 and MDA-MB-231 breast cancer cells. For this purpose, a pcDNA3.1 (+) vector with a GH gene insert was transfected by a liposomal agent in all breast cancer cells and then selection was conducted in neomycin (G418) included media. Autocrine GH-induced curcumin resistance was overcome in a dose-dependent manner and curcumin inhibited cell proliferation, invasion-metastasis and phosphorylation of p65 (Ser536), and thereby partly prevented its DNA binding activity in breast cancer cells. Moreover, curcumin induced caspase-mediated apoptotic cell death by activating the PA catabolic enzyme expressions, which led to generation of toxic by-products such as H2O2 in MCF-7, MDA-MB-453 and MDA-MB-231 GH+ breast cancer cells. In addition, transient silencing of SSAT prevented curcumin-induced cell viability loss and apoptotic cell death in each breast cancer cells. In conclusion, curcumin could overcome the GH-mediated resistant phenotype via modulating cell survival, death-related signaling routes and activating PA catabolic pathway.
- YayınSadece MetadataCurcumin Prevented Human Autocrine Growth Hormone (GH) Signaling Mediated NF-κB Activation and miR-183-96-182 Cluster Stimulated Epithelial Mesenchymal Transition in T47D Breast Cancer Cells(2019-02) Obakan Yerlikaya, Pınar; Çoker Gürkan, Ajda; Bulut, Derya; Genç, Recep; Arısan, Elif Damla; Ünsal, Zeynep Narçin; Palavan-Unsal, Narcin; 156421Autocrine growth hormone (GH) signaling is a promoting factor for breast cancer via triggering abnormal cell growth, proliferation, and metastasis, drug resistance. Curcumin (diferuloylmethane), a polyphenol derived from turmeric (Curcuma longa), has anti-proliferative, anti-carcinogenic, anti-hormonal effect via acting on PI3K/Akt, NF-κB and JAK/STAT signaling. Forced GH expression induced epithelial mesenchymal transition (EMT) through stimulation of miR-182-96-183 cluster expression in breast cancer cells. This study aimed to investigate the role of NF-κB signaling and miR-182-96-183 cluster expression profile on autocrine GH-mediated curcumin resistance, which was prevented by time-dependent curcumin treatment in T47D breast cancer cells. Dose- and time-dependent effect of curcumin on T47D wt and GH+breast cancer cells were evaluated by MTT cell viability and trypan blue assay. Apoptotic effect of curcumin was determined by PI and Annexin V/PI FACS flow analysis. Immunoblotting performed to investigate the effect of curcumin on PI3K/Akt/MAPK, NF-κB signaling. miR182-96-183 cluster expression profile was observed by qRT-PCR. Overexpression of GH triggered resistant profile against curcumin (20 µM) treatment for 24 h, but this resistance was accomplished following 48 h curcumin exposure. Concomitantly, forced GH induced invasion and metastasis through EMT and NF-κB activation were prevented by long-term curcumin exposure in T47D cells. Moreover, 48 h curcumin treatment prevented the autocrine GH-mediated miR-182-96-183 cluster expression stimulation in T47D cells. In consequence, curcumin treatment for 48 h, prevented autocrine GH-triggered invasion-metastasis, EMT activation through inhibiting NF-κB signaling and miR-182-96-183 cluster expression and induced apoptotic cell death by modulating Bcl-2 family members in T47D breast cancer cells.
- YayınSadece MetadataCyclin Dependent Kinase Inhibitors Modulates Polyamine Metabolism in MDA-MB-231 Cells(2010) Ünsal, Zeynep Narçin; Arısan, Elif Damla; Obakan Yerlikaya, Pınar; Çoker Gürkan, Ajda; Özdemir, İpek; 6125; 113920; 156421; 125860
- YayınSadece MetadataCyclin-dependent kinase inhibitors, roscovitine and purvalanol, induce apoptosis and autophagy related to unfolded protein response in HeLa cervical cancer cells(Springer, Van Godewijckstraat 30, 3311 Gz Dordrecht, Netherlands, 2018-10) Özfiliz Kılbaş, Pelin; Sarıkaya, Bahar; Obakan Yerlikaya, Pınar; Çoker Gürkan, Ajda; Arısan, Elif Damla; Temizci, Benan; Palavan Ünsal, Zeynep Narçın; 195744; 156421; 125860; 113920; 280081; 6125Roscovitine (Rosc) and purvalanol (Pur) are competitive inhibitors of cyclin-dependent kinases (CDKs) by targeting their ATP-binding pockets. Both drugs are shown to be effective to decrease cell viability and dysregulate the ratio of pro- and anti-apoptotic Bcl-2 family members, which finally led to apoptotic cell death in different cancer cell lines in vitro. It was well established that Bcl-2 family members have distinct roles in the regulation of other cellular processes such as endoplasmic reticulum (ER) stress. The induction of ER stress has been shown to play critical role in cell death/survival decision via autophagy or apoptosis. In this study, our aim was to investigate the molecular targets of CDK inhibitors on ER stress mechanism related to distinct cell death types in time-dependent manner in HeLa cervical cancer cells. Our results showed that Rosc and Pur decreased the cell viability, cell growth and colony formation, induced ER stress-mediated autophagy or apoptosis in time-dependent manner. Thus, we conclude that exposure of cells to CDK inhibitors induces unfolded protein response and ER stress leading to autophagy and apoptosis processes in HeLa cervical cancer cells.
- YayınSadece MetadataCytokine network is critical in growth hormone-induced resistance mechanism against curcumin which modulates JAK/STAT/SOCS pathway in MDA-MB-231 and MCF-7 breast cancer cells(2016) Çelik, Merve; Çoker Gürkan, Ajda; Arısan, Elif Damla; Obakan Yerlikaya, Pınar; Ünsal, Zeynep Narçin; 125860; 113920; 156421; 6125