Ceren Korkmaz - Academia.edu (original) (raw)

Papers by Ceren Korkmaz

Journal of Cancer, 2015

Discoidin Domain Receptors (DDR1/DDR2) are tyrosine kinase receptors which are activated by colla... more Discoidin Domain Receptors (DDR1/DDR2) are tyrosine kinase receptors which are activated by collagen. DDR signalling regulates cell migration, proliferation, apoptosis and matrix metalloproteinase (MMP) production. MMPs degrade extracellular matrix (ECM) and play essential role in tumor growth, invasion and metastasis. Nitrogen-containing bisphosphonates (N-BPs) which strongly inhibit osteoclastic activity are commonly used for osteoporosis treatment. They also have MMP inhibitory effect. In this study, we aimed to investigate the effects of zoledronate in PC3 cells and the possible role of DDR signalling and downstream pathways in these inhibitory effects. We studied messenger RNA (mRNA) and protein expressions of MMP-2,-9,-8, DDR1/DDR2 type I procollagen (TIP) and mRNA levels of PCA-1, MMP-13 and DDR-initiated signalling pathway players including K-Ras oncogene, ERK1, JNK1, p38, AKT-1 and BCLX in PC3 cells in the presence or absence of zoledronate (10-100 μM) for 2-3 days. Zoledro...

Experimental and Therapeutic Medicine, 2014

Prostate cancer is the second leading cause of morbidity and mortality in males in the Western wo... more Prostate cancer is the second leading cause of morbidity and mortality in males in the Western world. In the present study, LNCaP, which is an androgen receptor-positive and androgen-responsive prostate cancer cell line derived from lymph node metastasis, and DU145, which is an androgen receptor-negative prostate cancer cell line derived from brain metastasis, were investigated. TNFα treatment decreased p105 and p50 expression and R1881 treatment slightly decreased p105 expression but increased p50 expression with or without TNFα induction. As an aggressive prostate cancer cell line, DU145 transfected with six transmembrane protein of prostate (STAMP)1 or STAMP2 was also exposed to TNFα. Western blotting indicated that transfection with either STAMP gene caused a significant increase in NFκB expression following TNFα induction. In addition, following the treatment of LNCaP cells with TNFα, reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed with a panel of apoptosis-related gene primers. The apoptosis-related genes p53, p73, caspase 7 and caspase 9 showed statistically significant increases in expression levels while the expression levels of MDM2 and STAMP1 decreased following TNFα induction. Furthermore, LNCaP cells were transfected with a small interfering NFκB (siNFκB) construct for 1 and 4 days and induced with TNFα for the final 24 h. RT-qPCR amplifications were performed with apoptosis-related gene primers, including p53, caspases and STAMPs. However, no changes in the level of STAMP2 were observed between cells in the presence or absence of TNFα induction or between those transfected or not transfected with siNFκB; however, the level of STAMP1 was significantly decreased by TNFα induction, and significantly increased with siNFκB transfection. Silencing of the survival gene NFκB caused anti-apoptotic STAMP1 expression to increase, which repressed p53, together with MDM2. NFκB silencing had varying effects on a panel of cancer regulatory genes. Therefore, the effective inhibition of NFκB may be critical in providing a targeted pathway for prostate cancer prevention. CEREN GONEN-KORKMAZ, GULNUR SEVIN, GOKSEL GOKCE, MEHMET ZUHURI ARUN, GOKCE YILDIRIM, BUKET REEL, AYSEGUL KAYMAK and DENIZ OGUT Abbreviations: MDM2, E3 ubiquitin ligase; TNF, tumor necrosis factor; NFκB, nuclear factor κB; STEAP, six transmembrane epithelial antigen of prostate; STAMP, six transmembrane protein of prostate

The Journal of Steroid Biochemistry and Molecular Biology, 2014

It has been reported that NKX3.1 an androgen-regulated homeobox gene restricted to prostate and t... more It has been reported that NKX3.1 an androgen-regulated homeobox gene restricted to prostate and testicular tissues, encodes a homeobox protein, which transcriptionally regulates oxidative damage responses and enhances topoisomerase I re-ligation by a direct interaction with the ATM protein in prostate cells. In this study, we aimed to investigate the role of NKX3.1 in DNA double-strand break (DSB) repair. We demonstrate that the DNA damage induced by CPT-11 (irinotecan, a topo I inhibitor), doxorubicin (a topo II inhibitor), and H 2 O 2 (a mediator of oxidative damage), but not by etoposide (another topo II inhibitor), is negatively influenced by NKX3.1 expression. We also examined ␥H2AX (S139) foci formation and observed that the overexpression of NKX3.1 resulted a remarkable decrease in the formation of ␥H2AX (S139) foci. Intriguingly, we observed in NKX3.1 silencing studies that the depletion of NKX3.1 correlated with a significant decrease in the levels of p-ATM (S1981) and ␥H2AX (S139) . The data imply that the DNA damage response (DDR) can be altered, perhaps via a decrease in the topoisomerase I re-ligation function; this is consistent with the physical association of NKX3.1 with DDR mediators upon treatment of both PC-3 and LNCaP cells with CPT-11. Furthermore, the depletion of NKX3.1 with siRNA resulted in a G1/S progression via the facilitation of an increase in E2F stabilization concurrent with the suppressed DDR. Thus, the topoisomerase I inhibitor-mediated DNA damage enhanced the physical association of NKX3.1 with ␥H2AX (S139) on the chromatin in LNCaP cells, whereas NKX3.1 in the soluble fraction was associated with p-ATM (S1981) and RAD50 in these cells. Overall, the data suggest that androgens and NKX3.1 expression regulate the progression of the cell cycle and concurrently activate the DDR. Therefore, androgen withdrawal may facilitate the development of an error-prone phenotype and, subsequently, the loss of DNA damage control during prostate cancer development.

Oncogene, 2005

... prostate cancer. Ceren G Korkmaz 1,5 , Kemal S Korkmaz 1,5 , Piotr Kurys 1,5 , Cem Elbi 2 , L... more ... prostate cancer. Ceren G Korkmaz 1,5 , Kemal S Korkmaz 1,5 , Piotr Kurys 1,5 , Cem Elbi 2 , Ling Wang 1 , Tove I Klokk 1 , Clara Hammarstrom 3 , Gunhild Troen 4 , Aud Svindland 3 , Gordon L Hager 2 and Fahri Saatcioglu 1. ...

Molecular Carcinogenesis, 2014

As a link between inflammation and cancer has been reported in many studies, we established an in... more As a link between inflammation and cancer has been reported in many studies, we established an in vitro model of prostatic inflammation to investigate the loss of androgen receptor (AR)-mediated signaling in androgen responsive prostate cell lines. First, the U937 monocyte cell line was differentiated into macrophages using phorbol acetate (PMA), and cells were induced with lipopolysaccharide (LPS) for cytokine secretion. Next, the cytokine levels (TNFa, IL-6, and IL1b) in conditioned media (CM) were analyzed. Prostate cells were then fed with CM containing varying concentrations of TNFa, and IkB degradation, nuclear factor kappa B (NFkB) translocation and transactivation, and the expression of matrix metalloproteinase-8 (MMP8) and matrix metalloproteinase-9 (MMP9) were then assessed. As a result of CM treatment, ubiquitin-mediated AR degradation, which was restored using anti-TNFa antibody neutralization, led to both a decrease in KLK4, PSA, and NKX3.1 expression levels and the upregulation of GPX2. In addition to the loss of AR, acute and chronic CM exposure resulted in p53 degradation and consequent p21 downregulation, which was also restored by either androgen administration or ectopic NKX3.1 expression via the stabilization of MDM2 levels in LNCaP cells. Additionally, CM treatment enhanced H2AX (S139) phosphorylation (a hallmark of DNA damage) and genetic heterogeneity in the absence of androgens in prostate cells without activating mitochondrial apoptosis. Thus, the data suggest that inflammatory cytokine exposure results in the loss of AR and p53 signaling in prostate cells and facilitates genetic heterogeneity via ROS accumulation to promote prostate carcinogenesis.

Lupus, 2007

... Lupus http://lup.sagepub.com/content/16/4/289 The online version of this article can be found... more ... Lupus http://lup.sagepub.com/content/16/4/289 The online version of this article can be found at: DOI: 10.1177/0961203307078001 2007 16: 289 Lupus C. Korkmaz, DU Cansu and T. Kasifoglu report and clinical analysis of the literature 35 years of age) with systemic lupus ...

Lupus, 2003

Antiphospholipid syndrome (APS) is the association between antiphospholipid antibodies, venous an... more Antiphospholipid syndrome (APS) is the association between antiphospholipid antibodies, venous and arterial thrombosis and pregnancy morbidity. Although the kidney may be affected in APS, the treatment of renal involvement is yet to be elucidated. This report describes the clinical and laboratory features of four patients with primary APS nephropathy, and the beneficial effect of immunosuppressive therapy accompanied by warfarin and angiotensin-converting enzyme inhibitor. We also briefly discuss the possible mechanisms of the beneficial effects of immunosuppressives on primary APS nephropathy.

The Journal of Urology, 2004

Purpose: NKX3.1 is an androgen regulated gene that is largely specific to the prostate for expres... more Purpose: NKX3.1 is an androgen regulated gene that is largely specific to the prostate for expression and it is predicted to encode a homeobox protein. Null alleles of NKX3.1 in mice results in impaired prostate development as well as hyperplasia and dysplasia of the prostate. In addition, the NKX3.1 gene maps to a region of high loss of heterozygosity in prostate cancer in humans, suggesting that NKX3.1 might have a direct role in prostate carcinogenesis, possibly functioning as a tumor suppressor protein. Previous studies of the levels of NKX3.1 mRNA or protein in prostate cancer specimens have resulted in conflicting findings.

Journal of Endocrinology, 2004

Androgens are critical in the development and maintenance of the male reproductive system and imp... more Androgens are critical in the development and maintenance of the male reproductive system and important in the progression of prostate cancer. The effects of androgens are mediated by the androgen receptor (AR), which is a ligand-modulated transcription factor that belongs to the nuclear receptor superfamily. We and others have previously shown that CREB-binding protein (CBP) can function as a coactivator for AR. Similar to some other nuclear receptor coactivators and/or the proteins that they interact with, CBP has histone acetyl transferase (HAT) activity that is thought to contribute to transcriptional activation by nuclear receptors. We have therefore assessed whether an increase in the histone acetylation status in the cell can influence AR transcriptional activity, by using the histone deacetylase (HDAC) inhibitors (HDACIs) trichostatin A (TSA), sodium butyrate (Na-But) and depsipeptide (FR901228). We found that inhibition of HDAC activity significantly increased the ability of endogenous AR in LNCaP cells, or ectopically expressed AR in HeLa cells, to activate transcription from AR-dependent reporter constructs. In addition, HDACIs increased the androgen-dependent activation of the prostate-specific antigen (PSA) gene in LNCaP cells, an increase that was not due to an increase in nuclear AR protein levels. Moreover, the viral oncoprotein E1A that inhibits CBP HAT activity fully repressed the ability of HDACIs to stimulate AR-mediated transcription, indicating that CBP is involved in this process. Deletional mutagenesis of AR indicated that whereas the AF-2 domain in the C-terminus is dispensable, the AF-1 domain in the N-terminus is required for augmentation of AR action by HDACIs, an observation which is in concordance with the reduced ability of CBP to activate AR N-terminal deletion mutants. Furthermore, HDACI treatment rescued the deficiency in the transactivation potential of AF-2 mutants. Taken together, our findings suggest that a change in the level of histone acetylation of target genes is an important determinant of AR action, possibly mediated by CBP.

Molecular and cellular endocrinology, Jan 5, 2012

We recently reported that hematological and neurological expressed 1 (HN1) is a ubiquitously expr... more We recently reported that hematological and neurological expressed 1 (HN1) is a ubiquitously expressed, EGF-regulated gene. Expression of HN1 in prostate cell lines down-regulates PI3K-dependent Akt activation. Here, we investigate whether HN1 is regulated by androgens through the putative androgen response elements (AREs) found in its promoter. Knockdown of HN1 expression by siRNA silencing leads to an increase in Akt((S473)) phosphorylation, resulting in the translocation of androgen receptor (AR) to the nucleus; these effects can be abrogated by the non-specific Akt inhibitor LY294002 but not by the ERK inhibitor PD98059. Furthermore, HN1 overexpression correlates with an increase in ubiquitination-mediated degradation (a consequence of the decrease in S213/210 phosphorylation of AR), ultimately resulting in the down-regulation of AR-mediated expression of the KLK3, KLK4, NKX3.1 and STAMP2 genes. We also found that HN1 overexpression suppresses colony formation as well as R1881-m...

Gene, 2000

NKX3A (NKX3.1) is a recently identified androgen-regulated gene that is largely specific to prost... more NKX3A (NKX3.1) is a recently identified androgen-regulated gene that is largely specific to prostate for expression and likely to code for a homeobox protein. Here we report the full-length mRNA and genomic organization of human NKX3.1. There are at least five different splice variants of NKX3.1 mRNA that result in different open reading frames (ORFs). There is extensive similarity between the human and the mouse NKX3.1 cDNA sequences outside of the ORFs (greater than 60% overall identity), which may be involved in modulating NKX3.1 expression. In addition to its androgen regulation in the prostate cancer cell line LNCaP, we show that NKX3.1 expression is androgen-dependent in the CWR22 prostate cancer xenograft model. Interestingly, NKX3.1 is highly expressed in the androgen-independent derivative CWR22R in the absence of androgens, indicating that it may be deregulated in advanced prostate cancer. Using a Green Flourescent Protein fusion construct, we show that NKX3.1 is a nuclear protein consistent with its proposed function as a homeobox transcription factor. Furthermore, in addition to androgens, NKX3.1 expression is up-regulated by 17b-estradiol, but not by progesterone, dexamethasone, or 3,5,3∞-triiodothyronine in LNCaP cells. Regulation of NKX3.1 by androgens and 17b-estradiol in prostate cancer cells and its deregulation in androgen-independent prostate cancer suggest that it may have important regulatory roles during prostate cancer progression.

DNA and Cell Biology, 2000

Nuclear receptors form a superfamily of ligand-activ ated transcription factors. In contrast to t... more Nuclear receptors form a superfamily of ligand-activ ated transcription factors. In contrast to the significant advances made in recent years to dissect nuclear receptor structure and their corresponding function, progress has been rather slow in the identification of target genes for nuclear receptors, information that is a prerequisite for understanding hormone action. Here, we describe a simple screening protocol that makes it possible to efficiently and effectively clone hormone-responsive genes that are specific to a tissue of interest. When this procedure was used to clone prostate-specific and androgen-responsive genes, approxim ately 40% of the clones selected at random represented genes that are known to be androgen regulated and are largely specific to prostate for expression, such as prostate specific antigen (PSA). A further 37% are known to be highly enriched in prostate for expression, but their androgen regulation is yet to be studied. The rest of the clones represented novel genes, expressed sequence tags, or known genes whose possible androgen regulation has not yet been assessed. This screening scheme can be applied to any hormone/ligand to clone differentially expressed genes specific to a tissue of interest. Identification of such genes and their characterization should greatly facilitate understanding hormone action in normal and pathological conditions.

DNA and Cell Biology, 2001

The tissue kallikreins (KLKs) form a family of serine proteases that are involved in processing o... more The tissue kallikreins (KLKs) form a family of serine proteases that are involved in processing of polypeptide precursors and have important roles in a variety of physiologic and pathological processes. Common features of all tissue kallikrein genes identified to date in various species include a similar genomic organization of five exons, a conserved triad of amino acids for serine protease catalytic activity, and a signal peptide sequence encoded in the first exon. Here, we show that KLK4/KLK-L1/prostase/ARM1 (hereafter called KLK4) is the first significantly divergent member of the kallikrein family. The exon predicted to code for a signal peptide is absent in KLK4, which is likely to affect the function of the encoded protein. Green fluorescent protein (GFP)-tagged KLK4 has a distinct perinuclear localization, suggesting that its primary function is inside the cell, in contrast to the other tissue kallikreins characterized so far that have major extracellular functions. There are at least two differentially spliced, truncated variants of KLK4 that are either exclusively or predominantly localized to the nucleus when labeled with GFP. Furthermore, KLK4 expression is regulated by multiple hormones in prostate cancer cells and is deregulated in the androgen-independent phase of prostate cancer. These findings demonstrate that KLK4 is a unique member of the kallikrein family that may have a role in the progression of prostate cancer. 435

DNA and Cell Biology, 2011

As the molecular mechanism of b-catenin deregulation is not well understood, and stabilized b-cat... more As the molecular mechanism of b-catenin deregulation is not well understood, and stabilized b-catenin is known to translocate into the nucleus and activate genes for proliferation, a novel regulatory factor, hematological and neurological expressed 1 (HN1), for Akt-GSK3b-b-catenin axis is reported here. In our studies, HN1 gene structure was characterized. HN1 expression was found to be epidermal growth factor-responsive in PC-3 cells, and protein expression was also upregulated in PC-3 and LNCaP but not in DU145 cells. Additionally, HN1 was found to be downregulated by the specific AKT inhibitor wortmannin but not with PI3K or MAPK inhibitors, LY294002 and PD98059, respectively, in PC-3 and MCF-7 cells. Further, siRNA-mediated knockdown of HN1 resulted in considerable increase in Akt (S473) and GSK3b (S9),(Y216) phosphorylations; moreover, subsequent accumulation of b-catenin, increase in c-myc expression, and nuclear accumulation of cyclin D1 were observed in PC-3 cells. Knockdown of HN1 also resulted in prolongation of G 1 phase in cell cycle, increasing tetraploidy, presumably because of cells escaping from abnormal mitosis in PC-3 cells. Consistently, overexpression of HN1 reversed the cell-cycle-specific observations, resulted in accumulation of cells in G 2 /M, and reduced the proliferation rate, which were investigated using flow cytometry and methylthiazol tetrazolium assays. As activating mutations of b-catenin have been demonstrated in late-stage tumors, and b-catenin stabilization was correlated with poor prognosis in previous reports, epidermal growth factor-upregulated HN1 expression might have a role in deregulating the AKT-GSK3b (S9) -mediated signaling as a novel compensating mechanism.

Current Opinion in Biotechnology, 2011

Naked plasmid DNA is a powerful tool for gene therapy, but it is rapidly eliminated from the circ... more Naked plasmid DNA is a powerful tool for gene therapy, but it is rapidly eliminated from the circulation after intravenous administration. Therefore, the development of optimized DNA delivery systems is necessary for its successful clinical use. Solid lipid nanoparticles (SLNs) exhibit high transfection efficiency with less toxic effect. The aim of this study was to prepare and characterize SLNs with appropriate properties for effective and safe DNA delivery. SLNs were prepared by modified microemulsion dilution technique using precirol, Tween80, lecithin, ethanol and distilled water. For providing cationic property Esterquat1 (N,N-di-((-steaorylethyl)-N,N-dimethylammonium chloride) or Dimethyldidodecyl-ammonium bromide (DDAB) was incorporated into the formulation. Optimal formulations were complexed with Green fluorescent protein encoding plasmid DNA (pDNA) (pCMV-C1) with high transcription promotor. DNA release and DNase protection activities were examined on agarose gel electrophoresis. Cytotoxicity was determined on mammalian cell lines. The size and zeta potential of primary SLNs were determined as between 41 and 135 nm and −18, 4 to −35, 9 mV, respectively. For further studies optimal SLN formulation was selected which showed high stability with low zeta potential and SLN-pDNA complexes were obtained. As a result, cationic SLN systems with appropriate particle size and zeta potential were developed and characterized for DNA delivery.

Biochemical and Biophysical Research Communications, 2011

Acta Radiologica, 2004

We report the case of a 42-year-old woman who presented with Addison's disease with wides... more We report the case of a 42-year-old woman who presented with Addison's disease with widespread abdomino-pelvic visceral calcifications due to secondary amyloidosis. AA amyloidosis and calcification were supported by histological evidence of liver tissue. To our knowledge, no other case with such extensive visceral calcification involving the adrenals, liver, ovaries, and renal secondary to amyloidosis has been published.

Prostate cancer studies focus on identification of androgen receptor (AR) regulated genes that ar... more Prostate cancer studies focus on identification of androgen receptor (AR) regulated genes that are also highly expressed in the prostate. As a promising candidate, STAMP family genes STAMP1/STEAP2, STAMP2/STEAP4 and STEAP3 are involved in apoptosis and the cell cycle in metastatic prostate cancer. Vascular NADPH oxidase generates superoxide and other ROS, which stimulates IkappaB degradation and NF-kB activation by subunits of NADPH oxidases, namely p47phox and p67phox induced by different stimuli such as hydrogen peroxide. Hydrogen peroxide increased the expression levels of p67phox. They also have a role in redox-sensitive genes such as STAMP gene family. Flow cytometry analysis of LNCaP cells was performed using Annexin V staining and apoptotic index charts were drawn. STAMP1 and STAMP2 showed total anti-oxidant capacity versus control with hydrogen peroxide incubation. Using siRNA technology in LNCaP cells expressing mutant p53 silencing of p53 showed significant increase in MDM2 and decrease of caspase 9 mRNA levels at RT-PCR. Silencing of STAMP2, a significant decrease in p47phox was shown but STAMP1 silencing counteracted this effect on Cu/ZnSOD expression.As a conclusion, STAMP proteins have effects on oxidative stress-induced genes with significant and opposite changes.