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Now showing 1 - 10 of 112
  • PublicationEmbargo
    Epibrassinolide-induced apoptosis regardless of p53 expression via activating polyamine catabolic machinery, a common target for androgen sensitive and insensitive prostate cancer cells
    (Wiley-Blackwell, 111 River St, Hoboken 07030-5774, Nj Usa, 2014-12) Çoker Gürkan, Ajda; Palavan Unsal, Narçin; ARISAN, ELİF DAMLA; YERLİKAYA, PINAR OBAKAN; 156421; 113920; 125860; 6125
    BACKGROUNDEpibrassinolide (EBR), is a member of the brassinosteroids (BR), has been shown as an apoptotic inducer in different cancer cell lines. We previously showed that EBR induced apoptosis by activating polyamine catabolic pathway, which lead to the accumulation of cytotoxic compounds such as hydrogen peroxide and aldehydes in LNCaP and DU 145 prostate cancer cells. However, we found that LNCaP prostate cancer cells expressing functional androgen receptor (AR) was found more sensitive to EBR than those with non-functional AR (DU 145 cells). RESULTSTo better understand the apoptotic effect of EBR, we aimed to investigate the cellular responses in p53 null, PC3 prostate cancer cells. We showed that EBR induced mitochondria-mediated and caspase-dependent apoptosis in wt and p53 stable transfected PC3 cells, which suggesting that EBR-induced apoptosis regardless of p53 expression. In addition, inhibition of p53 by pifithrin- orthe activation of Mdm2 by Nutlin-3 co-treatment did not alter EBR induced PARP cleavage. Furthermore, EBR treatment was also induced apoptosis in both LNCaP(wt p53) and DU 145 (mt p53)cells, respectively. These all findings verified that EBR-induced apoptosis regardless of p53 expression. The PA catabolic pathway was also altered in PC3 cells causing the generation of reactive oxygen species (ROS) and intracellular PA pool decrease. However, the silencing of spermidine-spermineacetyltransferase (SSAT), a key enzyme at polyamine catabolic machinery prevented the EBR-induced apoptosis. CONCLUSIONSTherefore, we concluded that EBR-induced apoptosis was mainly related with PA catabolic pathway and independent from p53 expression. Prostate 74: 1622-1633, 2014. (c) 2014 Wiley Periodicals, Inc.
  • PublicationOpen Access
    Atiprimod Triggered Apoptotic Cell Death Via Acting on PERK/eIF2 alpha/ATF4/CHOP and STAT3/NF-Kappa B axis in MDA-MB-231 and MDA-MB-468 Breast Cancer Cells
    Purpose The constitutive activation of STAT3 through receptor tyrosine kinases triggered breast cancer cell growth and invasion-metastasis. Atiprimod impacts anti-proliferative, anti-carcinogenic effects in hepatocellular carcinoma, lymphoma, multiple myeloma via hindering the biological activity of STAT3. Dose-dependent atiprimod evokes first autophagy as a survival mechanism and then apoptosis due to prolonged ER stress in pituitary adenoma cells. The therapeutic efficiency and mechanistic action of atiprimod in breast cancer cells have not been investigated yet. Thus, we aimed to modulate the pivotal role of ER stress in atiprimod-triggered apoptosis in MDA-MB-231 and MDA-MB-468 breast cancer cells. Results Dose- and time-dependent atiprimod treatment inhibits cell viability and colony formation in MDA-MB-468 and MDA-MB-231 breast cancer cells. A moderate dose of atiprimod (2 mu M) inhibited STAT3 phosphorylation at Tyr705 residue and also suppressed the total expression level of p65. In addition, nuclear localization of STAT1, 3, and NF-kappa B was prevented by atiprimod exposure in MDA-MB-231 and MDA-MB-468 cells. Atiprimod evokes PERK, BiP, ATF-4, CHOP upregulation, and PERK (Thr980), eIF2 alpha (Ser51) phosphorylation's. However, atiprimod suppressed IRE1 alpha-mediated Atg-3, 5, 7, 12 protein expressions and no alteration was observed on Beclin-1, p62 expression levels. PERK/eIF2 alpha/ATF4/CHOP axis pivotal role in atiprimod-mediated G1/S arrest and apoptosis via Bak, Bax, Bim, and PUMA upregulation in MDA-MB-468 cells. Moreover, atiprimod renders MDA-MB-231 more vulnerable to type I programmed cell death by plasmid-mediated increased STAT3 expression. Conclusion Atiprimod induced prolonged ER stress-mediated apoptosis via both activating PERK/eIF2 alpha/ATF4/CHOP axis and suppressing STAT3/NF-kappa B transcription factors nuclear migration in TBNC cells.
  • PublicationOpen Access
    In Vitro Investigations of miR-33a Expression in Estrogen Receptor-Targeting Therapies in Breast Cancer Cells
    (MDPI, 2021) KILBAŞ, PELİN ÖZFİLİZ; SÖNMEZ, ÖZLEM; Çoker-Gürkan, Ajda; Palavan-Ünsal, Narcin; Uysal-Onganer, Pınar; ARISAN, ELİF DAMLA; YERLİKAYA, PINAR OBAKAN
    Simple Summary: Altered metabolic pathways determine the aggressivity of breast cancer cells. To highlight the potential markers gains importance to understand early molecular signatures of disease. microRNAs are the small non-coding RNAs found in different biological samples. Due to the dysregulation of metabolic pathways, the expression and secretion of microRNAs are modulated. (1) Background: Increased fatty acid synthesis leads to the aggressive phenotype of breast cancer and renders efficiency of therapeutics. Regulatory microRNAs (miRNAs) on lipid biosynthesis pathways as miR-33a have potential to clarify the exact mechanism. (2) Methods: We determined miR-33a expression levels following exposure of MCF-7 and MDA-MB-231 breast cancer cells to estrogen receptor (ER) activator (estradiol-17 beta, E2) or anti-estrogens (ICI 182,780, Fulvestrant, FUL) at non-cytotoxic concentrations. We related miR-33a expression levels in the cells to cellular lipid biosynthesis-related pathways through immunoblotting. (3) Results: miR-33a mimic treatment led to significantly downregulation of fatty acid synthase (FASN) in MCF-7 cells but not in MDA-MB-231 cells in the presence of estradiol-17 beta (E2) or Fulvestrant (FUL). In contrast to the miR-33a inhibitor effect, miR-33a mimic co-transfection with E2 or FUL led to diminished AMP-activated protein kinase a (AMPKa) activity in MCF-7 cells. E2 increases FASN levels in MDA-MB-231 cells regardless of miR-33a cellular levels. miR-33a inhibitor co-treatment suppressed E2-mediated AMPKa activity in MDA-MB-231 cells. (4) Conclusions: The cellular expression levels of miR-33a are critical to understanding differential responses which include cellular energy sensors such as AMPKa activation status in breast cancer cells.
  • Publication
    Investigation of PI3K-AKT and EMT-targeted miRNA profiles in palbociclib-treated Panc-1 and MiaPaCa-2 pancreatic cancer cells
    (2019-07) Çoker Gürkan, Ajda; YERLİKAYA, PINAR OBAKAN; RENCÜZOĞULLARI, ÖZGE; 222563; 156421; 125860
    The therapeutic strategies of pancreatic cancer (PC) are with the various combination treatment of anti-cancer drugs still in progress. However, the survival rate o f PC is still under 6%. because o f the limited therapeutics and no controllable prognosis. miRNAs have an important role in tire regulation of metabolic cascades which are critical in the differentiation of PC progression. In the current study, we aimed to investigate the role o f palbociclib (CDK4/6 inhibitor) on aberrantly activated pathways, PI3K/AKT, and EMT signaling axis through differently expressed miRNA profiles in Pane-1 and MiaPaCa-2 cells. The effect of palbociclib on cell viability was detennined by MTT cell viability test in time and dose-dependent maimer in PC cells. The expression profiles were analyzed by RT-PCR. We found that palbociclib effectively reduced cell viability and proliferation for following exposure of Panc-1 and MiaPaCa-2 cells for 24h. Additively, Panc-1 and MiaPaCa-2 cells were sensitive to palbociclib with the significant blockade in the G1 phase o f the cell cycle. Palbociclib decreased the expression o f PI3K and p-AKT in PC cells. Moreover, palbociclib downregulated the levels of B-catenin in Panc-1 cells, but not in MiaPaCa-2 cells. Palbociclib treatment led to increased levels of tumor suppressor miR- 506, miR-100, and miR-141 in MiaPaCa-2 cells, while the only detectable increase in tumor suppressor miRNA was detected formiR-100 levels in Panc-1 cells. Additionally, the oncomir miR-208 increased after palbociclib treatment in MiaPaCa-2 cells. In conclusion, palbociclib induced cell cycle arrest and reduced cell viability. However, palbociclib had a various effect on the regulation of PI3K/AKT and EMT signaling in each PC cell line. Investigating the effect of palbociclib on the tumor suppressor and oncomir miRNA profiles is a new therapeutic strategy to reduce cell viability and metastatic process of pancreatic cancer.
  • PublicationRestricted
    Epibrassinolide-Induced Autophagy Occurs in an Atg5-Independent Manner Due to Endoplasmic Stress Induction in MEF Cells
    (Springer, 2020) Adacan, Kaan; YERLİKAYA, PINAR OBAKAN; Çoker-Gürkan, Ajda; Kaya, Resul İsmail; Palavan-Ünsal, Narcin; ARISAN, ELİF DAMLA
    Epibrassinolide (EBR), a polyhydroxysteroid belongs to plant growth regulator family, brassinosteroids and has been shown to have a similar chemical structure to mammalian steroid hormones. Our findings indicated that EBR could trigger apoptosis in cancer cells via induction of endoplasmic reticulum (ER) stress, caused by protein folding disturbance in the ER. Normal cells exhibited a remarkable resistance to EBR treatment and avoid from apoptotic cell death. The unfolded protein response clears un/misfolded proteins and restore ER functions. When stress is chronic, cells tend to die due to improper cellular functions. To understand the effect of EBR in non-malign cells, mouse embryonic fibroblast (MEF) cells were investigated in detail for ER stress biomarkers, autophagy, and polyamine metabolism in this study. Evolutionary conserved autophagy mechanism is a crucial cellular process to clean damaged organelles and protein aggregates through lysosome under the control of autophagy-related genes (ATGs). Cells tend to activate autophagy to promote cell survival under stress conditions. Polyamines are polycationic molecules playing a role in the homeostasis of important cellular events such as cell survival, growth, and, proliferation. The administration of PAs has been markedly extended the lifespan of various organisms via inducing autophagy and inhibiting oxidative stress. Our data indicated that ER stress is induced following EBR treatment in MEF cells as well as MEF Atg5(-/-) cells. In addition, autophagy is activated following EBR treatment by targeting PI3K/Akt/mTOR in wildtype (wt) cells. However, EBR-induced autophagy targets ULK1 in MEF cells lacking Atg5 expression. Besides, EBR treatment depleted the PA pool in MEF cells through the alterations of metabolic enzymes. The administration of Spd with EBR further increased autophagic vacuole formation. In conclusion, EBR is an anticancer drug candidate with selective cytotoxicity for cancer cells, in addition the induction of autophagy and PA metabolism are critical for responses of normal cells against EBR.
  • Publication
    Fetuin-A 742 (C/T) and 766 (C/G) polymorphic sites are associated with increased risk of myocardial infarction in older patients (40 years of age)
    (Spandidos Publ Ltd, Pob 18179, Athens, 116 10, Greece, 2015-07) Çoker Gürkan, Ajda; Palavan Ünsal, Zeynep Narçın; ARISAN, ELİF DAMLA; GENÇ, SELMA; YERLİKAYA, PINAR OBAKAN; COŞKUN, DENİZ; 125860; 113920; 156421; 6125
    Inflammation and genetics have key roles in the pathogenesis of atherosclerosis, and the etiology of myocardial infarction (MI). Recent studies have indicated that lower serum levels of fetuin-A may accelerate the vascular mineralization process, which leads to pathophysiological conditions, such as coronary heart disease and chronic renal failure. The aim of the present study was to evaluate the association between specific fetuin-A polymorphisms (742 and 766) that are associated with circulating serum levels, and MI cases. The study consisted of 292 participants; 146 healthy control subjects and 146 patients with MI. The patient group was divided into two subgroups: 56 MI40 years and 90 MI40 years. The genotype distribution of fetuin 742 (C/T) and fetuin 766 (C/G) were determined by restriction enzyme digestion of polymerase chain reaction products. A significant difference was determined between the patients with MI and the control subjects with regards to fetuin-A 742 C/T gene polymorphism (P=0.028), regardless of age. Genotype distributions of fetuin-A 742 (C/G, P= 0.004) and 766 (C/T, P=0.017) were statistically different in the older patients with MI (MI40 years old), as compared with the healthy controls; however, there were no significant differences between the younger patients with MI and the controls, with regards to fetuin-A 742 C/T (P=0.519) and 766 C/G (P=0.653) gene polymorphisms. In addition, an association was observed between the presence of fetuin-A 742 T and 766 G alleles, and MI cases. The present study demonstrates that fetuin-A 742 (C/T) and 766 (C/G) genotypes may be risk factors for MI in patients older than 40 years of age.
  • Publication
    DENSpm overcame Bcl-2 mediated resistance against Paclitaxel treatment in MCF-7 breast cancer cells via activating polyamine catabolic machinery
    (Elsevier France-Editions Scientifiques Medicales Elsevier, 23 Rue Linois, 75724 Paris, France, 2016-12) Akyol, Zeynep; Çoker Gürkan, Ajda; Palavan Ünsal, Zeynep Narçın; ARISAN, ELİF DAMLA; YERLİKAYA, PINAR OBAKAN; 125860; 113920; 156421; 6125
    Purpose: The Bcl-2 mediated resistance is one of the most critical obstacle in cancer therapy. Conventional chemotherapeutics such as Paclitaxel, a commonly used in the treatment of metastatic breast cancer, is not sufficient to overcome Bcl-2 mediated drug resistance mechanism. Thus, combinational drug regimes are favored by researchers to overcome resistance phenotype against drugs. N1, N11-diethylnorspermine (DENSpm), a polyamine analogue, which is a promising drug candidate induced-cell cycle arrest and apoptosis in various cancer cells such as prostate, melanoma, colon and breast cancer cells via activated polyamine catabolism and reactive oxygen generation. Recent studies indicated the potential therapeutic role of DENSpm in phase I and II trials in breast cancer cases. Although the molecular targets of Paclitaxel in apoptotic cell death mechanism is well documented, the therapeutic effect of DENSpm and Paclitaxel in breast cancer cells has not been investigated yet. In this study, our aim was to determine the time dependent effect of DENSpm and Paclitaxel on apoptotic cell death via determination of polyamine metabolism related targets in wt and Bcl-2 overexpressing MCF-7 breast cancer cells. Results: In our experimental study, Paclitaxel decreased cell viability in dose-dependent manner within 24 h. Co-treatment of Paclitaxel (30 nM) with DENSpm (20 mu M) further increased the cytoxicity of Paclitaxel (30 nM) compared to alone Paclitaxel (30 nM) treatment in MCF-7 Bcl-2+ breast cancer cells. In addition, we determined that resistance against Paclitaxel-induced apoptotic cell death in Bcl-2 overexpressed MCF-7 cells was overcome due to activation of polyamine catabolic pathway, which caused depletion of polyamines. Conclusions: DENSpm combinational treatment might increase the effect of low cytotoxic paclitaxel in drug-resistant breast cancer cases. (C) 2016 Elsevier Masson SAS. All rights reserved.
  • Publication
    The combination of rapamycin with CDK inhibitors purvalanol and roscovitine induces autophagy by modulating different mTOR complexes in DU 145 prostate cancer cells
    (2014) Berrak, Özge; Çoker Gürkan, Ajda; Ünsal, Zeynep Narçin; ARISAN, ELİF DAMLA; YERLİKAYA, PINAR OBAKAN; 113920; 156421; 125860; 6125
  • Publication
    24-Epibrassinolide Induces SSAT and Causes Caspase-Dependent Apoptosis In Different Prostate Cancer Cell Lines
    (2011) Bolkent, Şehnaz; Ünsal, Zeynep Narçin; ARISAN, ELİF DAMLA; YERLİKAYA, PINAR OBAKAN; 156421; 113920; 3894; 6125
  • Publication
    The combination of rapamycin with purvalanol and roscovitine induces autophagy through PI3K/AKT and Ras/Raf/Erk pathways regulation in DU 145 prostate cancer cells
    (2014) Berrak, Özge; Çoker Gürkan, Ajda; Ünsal, Zeynep Narçin; ARISAN, ELİF DAMLA; YERLİKAYA, PINAR OBAKAN; 113920; 156421; 125860; 6125