Moleküler Biyoloji ve Genetik Bölümü / Department of Molecular Biology and Genetics

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24-Epibrassinolide Induces SSAT and Causes Caspase-Dependent Apoptosis In Different Prostate Cancer Cell Lines
(2011) Obakan Yerlikaya, Pınar; Arısan, Elif Damla; Bolkent, Şehnaz; Ünsal, Zeynep Narçin; 156421; 113920; 3894; 6125
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Activation of polyamine catabolic enzymes involved in diverse responses against epibrassinolide-induced apoptosis in LNCaP and DU145 prostate cancer cell lines
(Springer Wien, Sachsenplatz 4-6, Po Box 89, A-1201 Wien, Austria, 2014-03) Obakan, Pınar; Arısan, Elif Damla; Palavan Unsal, Narçin; Calcabrini, Annarica; Agostinelli, Enzo; Bolkent, Şehnaz; 156421; 113920; 6125; 3894
Epibrassinolide (EBR) is a biologically active compound of the brassinosteroids, steroid-derived plant growth regulator family. Generally, brassinosteroids are known for their cell expansion and cell division-promoting roles. Recently, EBR was shown as a potential apoptotic inducer in various cancer cells without affecting the non-tumor cell growth. Androgen signaling controls cell proliferation through the interaction with the androgen receptor (AR) in the prostate gland. Initially, the development of prostate cancer is driven by androgens. However, in later stages, a progress to the androgen-independent stage is observed, resulting in metastatic prostate cancer. The androgen-responsive or -irresponsive cells are responsible for tumor heterogeneity, which is an obstacle to effective anti-cancer therapy. Polyamines are amine-derived organic compounds, known for their role in abnormal cell proliferation as well as during malignant transformation. Polyamine catabolism-targeting agents are being investigated against human cancers. Many chemotherapeutic agents including polyamine analogs have been demonstrated to induce polyamine catabolism that depletes polyamine levels and causes apoptosis in tumor models. In our study, we aimed to investigate the mechanism of apoptotic cell death induced by EBR, related with polyamine biosynthetic and catabolic pathways in LNCaP (AR+), DU145 (AR-) prostate cancer cell lines and PNT1a normal prostate epithelial cell line. Induction of apoptotic cell death was observed in prostate cancer cell lines after EBR treatment. In addition, EBR induced the decrease of intracellular polyamine levels, accompanied by a significant ornithine decarboxylase (ODC) down-regulation in each prostate cancer cell and also modulated ODC antizyme and antizyme inhibitor expression levels only in LNCaP cells. Catabolic enzymes SSAT and PAO expression levels were up-regulated in both cell lines; however, the specific SSAT and PAO siRNA treatments prevented the EBR-induced apoptosis only in LNCaP (AR+) cells. In a similar way, MDL 72,527, the specific PAO and SMO inhibitor, co-treatment with EBR during 24 h, reduced the formation of cleaved fragments of PARP in LNCaP (AR+) cells.
Open Access
Aging-related diseases and autophagy
(2016) Arisan, Elif Damla; OBAKAN YERLIKAYA, PINAR; Çoker Gürkan , Ajda; Palavan Unsal, Narcin
Autophagy is fundamental, evolutionary conserved physiological process at molecular level which targets long-lived cytosolic proteins and organelles to be recycled through lysosomal degradation. Diminished autophagic activity caused cellular stress in many organisms following aging, and inhibition of autophagy in model organisms causes degenerative changes and pathologic diseases observed with high incidence ratio generally in older ages. Consequently the delayed senescence or increased longevity in model organisms often stimulate autophagy, and autophagy inhibition compromises anti-aging effects. The cytoprotective function of autophagy is presented in various human diseases such as lung, liver, cardiovascular diseases, neurodegeneration, myopathies, cancer, stroke, infections and metabolic diseases which are found associated with autophagic targets. These pathologies are defined with their age-dependent characteristics, is not fully understood that how autophagy network regulates metabolism and may cause diseases in age-related manner. In this book chapter, we are going to discuss the autophagy and aging relationship in three different parts. In the first section autophagy and aging relationship is going to be presented through explaining responsible signalling network. The autophagy and age-related neurological disorders, genetic basis of age-dependent diseases and the functional role of autophagy is going to be discussed in the second and third part of the chapter.
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An investigation on regulation on trichome metabolism related genes against salt stress in soybean (Glycine max L. Merr.)
(2014-06-25) Çelik, Özge; Atak, Çimen; Suludere, Zekiye; 113987; 6653; 4019
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Anti-metastatic effect of ranolazine in an in vivo rat model of prostate cancer, and expression of voltage-gated sodium channel protein in human prostate
(2019-03-20) Altun, Seyhan; Bugan, İlknur; Küçük, Selma; Karagöz, Zeynep; Fraser, SP; Kaya, Handan; Dodson; Foster, Cs; Djamgoz, Mba; 4995
Background Voltage-gated Na+ channels (VGSCs) are functionally upregulated in rat and human prostate cancer (PCa) where channel activity promotes cellular invasiveness in vitro and metastasis in vivo. Ranolazine is a clinically used VGSC inhibitor/anti-anginal drug, which has been shown previously to inhibit breast cancer metastasis in vivo. Methods Using the Dunning model of rat PCa, the effect of ranolazine applied systemically (by gavage) was tested on the development of primary tumours and metastases following subcutaneous inoculation of Mat-LyLu cells into Copenhagen rats. In addition, human prostate tissue microarrays were used to determine VGSC protein expression in cancerous versus non-cancerous tissue. Several public databases were searched to compare Nav1.7/ SCN9A expression levels in ‘normal’ vs. PCa tissues. Results Ranolazine (2.5 and 5 µM) decreased the number of lung metastases by up to 63%. In contrast, primary tumourigenesis was not affected. Ranolazine also reduced the percentage of cells in the metastases expressing Nav1.7, the main VGSC subtype expressed in PCa, but the expression level was higher. In prostate tissue microarrays, VGSC protein expression was significantly higher in cancerous versus non-cancerous tissue. There was no correlation between the VGSC expression and either prostate-specific antigen or Gleason score. In public databases, little information could be found on Nav1.7 protein expression in PCa. In addition, the database information on Nav1.7 mRNA (SCN9A) expression levels did not correlate with previously reported upregulation in PCa cells and tissues. Conclusions The main conclusions were (i) ranolazine inhibited metastasis and (ii) it was a subpopulation of cells with particularly high levels of Nav1.7 protein that reached the metastatic sites. These data extend earlier studies and suggest that Nav1.7 expression could serve as a functional biomarker of metastatic PCa and that VGSC blockers may be useful as antimetastatic agents.
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Antioxidative defense system differences to drought stress of tomato cultivars
(2014) Ayan, Alp; Çelik, Özge; Atak, Çimen; 185510; 113987; 6653
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Antioxidative defense system differences to drought stress of tomato cultivars
(Elsevier Science Bv, Po Box 211, 1000 Ae Amsterdam, Netherlands, 2014-09) Ayan, Alp; Çelik, Özge; Atak, Çimen; 185510; 113987; 6653
The aim of this study is to investigate the enzymatic and non-enzymatic responses of two different industrial tomato varieties (X5671R and 5MX12956) against drought stress. Fourteen-day-old seedlings were subjected to drought stress by non-watering and the stress was continued for 7 days. The effects of drought stress on tomato varieties analysed due to the results of biochemical analysis (total protein content, lipid peroxidation, relative water content, chlorophyll contents) and enzymatic activity and isozyme analysis of SOD, CAT, APX and POX. The highest water loss was recorded in X5671R as 73.17%. 64% total chlorophyll decrease was observed in both varieties on 7th day. Total protein, proline, malondialdehyde concentrations and antioxidant enzymes presented increase with related to increasing drought stress for both varieties. Due to the results, we concluded that 5MX12956 variety is more drought tolerant then X5671R. Isozyme densities and band differences were recorded. The densities of POX isozymes were started to increase from 5th day of stress. Fe-SOD, Cu/Zn-SOD1-2 isozyme bands were identified in X5671R variety, while 5MX12956 showed only Cu/Zn-SOD isozyme band. Differences in APX isozymes were observed from the 4th day of drought stress in both varieties. The results indicated the differences in antioxidant metabolism of tomato plants.
Embargo
Applications of Ionizing Radiation in Mutation Breeding
(InTech, 2017-05) Çelik, Özge; Atak, Çimen; 113987; 6653
As a predicted result of increasing population worldwide, improvements in the breeding strategies in agriculture are valued as mandatory. The natural resources are limited, and due to the natural disasters like sudden and severe abiotic stress factors, excessive floods, etc., the production capacities are changed per year. In contrast, the yield potential should be significantly increased to cope with this problem. Despite rich genetic diversity, manipulation of the cultivars through alternative techniques such as mutation breeding becomes important. Radiation is proven as an effective method as a unique method to increase the genetic variability of the species. Gamma radiation is the most preferred physical mutagen by plant breeders. Several mutant varieties have been successfully introduced into commercial production by this method. Combinational use of in vitro tissue culture and mutation breeding methods makes a significant contribution to improve new crops. Large populations and the target mutations can be easily screened and identified by new methods. Marker assisted selection and advanced techniques such as microarray, next generation sequencing methods to detect a specific mutant in a large population will help to the plant breeders to use ionizing radiation efficiently in breeding programs.
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Assessment 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; 173248
BackgroundSystemic 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.
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Association 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; 6125
Urolithiasis 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
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Association Between Sporadic Parkinson Disease And Interleukin-1 Beta-511 Gene Polymorphisms In The Turkish Population
(John Libbey Eurotext Ltd, 127 Ave De La Republique, 92120 Montrouge, France, 2010-06) Arman, Ahmet; Işık, Nihal; Candan, Fatma; Becit, Kezban Serap; List, Edward O.; Çoker, Ajda; TR173248; TR217343; TR125860; TR198466
The pathogenesis of Parkinson Disease (PD) remains poorly understood; however, inflammation is thought to play an important role in disease progression. Recent reports suggest that IL-1, a major proinflammatory cytokine, might play a role in PD progression. The purpose of this study was to determine the relationship between IL-1 gene family polymorphisms [IL-1 alpha (-889), IL-1Ra (VNTR) and IL-1 beta (-511, +3953)] and PD in the Turkish population. In this study, we examined the genotypes of IL-1 gene family polymorphisms in 365 individuals, of which 199 were healthy control subjects and 166 were PD patients. No significant differences were found in the genotype distribution or in the allele frequencies of IL-1 alpha (-889), IL-1Ra (VNTR) and IL-1 beta (+3953) between PD cases and control subjects. However, distribution of the IL-1 beta -511 2/2 (T/T) genotype was found to be significantly lower in PD patients than in healthy controls (p = 0.018, x(2): 8.242, OR: 2.211, 95% CI: 1.261-3.877). In addition, the IL-1 beta -511 allele 1 (C) frequency was significantly elevated in PD patients versus controls (p = 0.048, x(2): 3.87, OR: 1.178, 95% CI: 0.999-1.388). These results suggest that IL-1 alpha (-889), IL-1Ra and IL-1 beta (+3953) gene polymorphisms have no association with PD, while allele 1 (C) of IL-1 beta (-511) is associated with PD and may provide a susceptibility factor for this disease in the Turkish population. Furthermore, the 2/2 (T/T) genotype of IL-1 beta (-511) may protect individuals from PD.
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Atiprimod induce apoptosis in pituitary adenoma: Endoplasmic reticulum stress and autophagy pathways
(WILEY, 111 RIVER ST, HOBOKEN 07030-5774, NJ USA, 2019-12) Çoker Gürkan , Ajda; Ayhan Şahin, Burcu; Keçeoğlu, Gizem; OBAKAN YERLIKAYA, PINAR; Arisan, Elif Damla; Palavan Unsal, Narcin
Pituitary adenoma is the most common tumor with a high recurrence rate due to a hormone-dependent JAK/signal transducer and activator of transcriptions (STAT) signaling. Atiprimod, a novel compound belonging to the azaspirane class of cationic amphiphilic drugs, has antiproliferative, anticarcinogenic effects in multiple myeloma, breast, and hepatocellular carcinoma by blocking STAT3 activation. Therapeutic agents' efficiency depends on endoplasmic reticulum (ER) stress-autophagy regulation during drug-mediated apoptotic cell death decision. However, the molecular machinery of dose-dependent atiprimod treatment regarding ER stress-autophagy has not been investigated yet. Thus, our aim is to investigate the ER stress-autophagy axis in atiprimod-mediated apoptotic cell death in GH-secreting rat cell line (GH3) pituitary adenoma cells. Dose-dependent atiprimod treatment decreased GH3 cell viability, inhibited cell growth, and colony formation. Upregulation of Atg5, Atg12, Beclin-1 expressions, cleavage of LC-3II and formation of autophagy vacuoles were determined only after 1 mu M atiprimod exposure. In addition, atiprimod-triggered ER stress was evaluated by BiP, C/EBP-homologous protein (CHOP), p-PERK upregulation, and Ca+2 release after 1 mu M atiprimod exposure. Concomitantly, increasing concentration of atiprimod induced caspase-dependent apoptotic cell death via modulating Bcl(2) family members. Moreover, by N-acetyl cycteinc pretreatment, atiprimod triggered reactive oxygen species generation and prevented apoptotic induction. Concomitantly, dose-dependent atiprimod treatment decreased both GH and STAT3 expression in GH3 cells. In addition, overexpression of STAT3 increased atiprimod-mediated cell viability loss and apoptotic cell death through suppressing autophagy and ER stress key molecules expression profile. In conclusion, a low dose of atiprimod exposure triggers autophagy and mild-ER stress as a survival mechanism, but increased atiprimod dose induced caspase-dependent apoptotic cell death by targeting STAT3 in GH3 pituitary adenoma cells.
Open 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
(Springer, 2021) Çoker-Gürkan, Ajda; CAN, ESİN; ŞAHİN, SEMANUR; Obakan-Yerlikaya, Pınar; Arısan, Elif-Damla
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.
Open Access
Autocrine 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; 6125
Autocrine 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.
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Bag-1 promotes cell survival through c-Myc-mediated ODC upregulation that is not preferred under apoptotic stimuli in MCF-7 cells
(Wiley-Blackwell, 111 River St, Hoboken 07030-5774, NJ USA, 2015-07) Özfiliz Kılbaş, Pelin; Kızılboğa, Tuğba; Demir, Salih; Palavan Ünsal, Zeynep Narçın; Arısan, Elif Damla; Dinler Doğanay, Gizem; Alkurt, Gizem; 195744; 6125; 113920; 152975
Bag-1, Bcl-2 associated athanogene-1, is a multifunctional protein that can regulate a wide variety of cellular processes: proliferation, cell survival, transcription, apoptosis and motility. Bag-1 interacts with various targets in the modulation of these pathways; yet molecular details of Bag-1's involvement in each cellular event are still unclear. We first showed that forced Bag-1 expression promotes cell survival and prevents drug-induced apoptosis in MCF-7 breast cancer cells. Increased mRNA expressions of c-myc protooncogene and ornithine decarboxylase (ODC), biosynthetic enzyme of polyamines, were detected in Bag-1L+ cells, and western blots against the protein product of c-Myc and ODC confirmed these findings. Once ODC, a c-Myc target, gets activated, polyamine biosynthesis increases. We observed enhanced polyamine content in the Bag-1L+ cells. On the contrary, when polyamine catabolic mechanisms were investigated, Bag-1 silencing suppressed biosynthesis of polyamines because of the downregulation of ODC and upregulation of PAO. Exposure of cells to apoptotic inducers enhances the cell death mechanism by producing toxic products such as H2O2 and aldehydes. Bag-1L+ cells prevented drug-induced PAO activation leading to a decrease in H2O2 production following cisplatin or paclitaxel treatment. In this line, our results suggested that Bag-1 indirectly affects cell survival through c-Myc activated signalling that causes elevation of ODC levels, leading to an increase of the polyamine content. Copyright (c) 2015 John Wiley & Sons, Ltd.
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Bag-1 silencing enhanced apoptosis via altering the ubiquitination process of Foxo3a in MCP-7 breast cancer cells
(Spandidos Publ Ltd, Pob 18179, Athens, 116 10, Greece, 2017) Özfiliz Kılbaş, Pelin; Arısan, Elif Damla; Dinler Doğanay, Gizem; Palavan Ünsal, Zeynep Narçın; 195744; 113920; 152975; 6125
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Bag-1 Silencing Enhanced Chemotherapeutic Drug-induced Apoptosis in MCF-7 Breast Cancer Cells Affecting PI3K/Akt/mTOR and MAPK Signaling Pathways
(2019-01-19) Özfiliz Kılbaş, Pelin; Akçay, İzzet Mehmet; Dinler Doğanay, Gizem; Arısan, Elif Damla; 195744; 152975; 113920
The multifunctional anti-apoptotic Bag-1 protein has important roles in apoptosis, proteasome-mediated degradation, transcriptional regulation, and intracellular signaling. Bag-1 promotes cell survival and proliferation, and is overexpressed in breast cancer. Therefore, Bag-1-targeted therapy might be a promising strategy to treat breast cancer. However, the effects of Bag-1 silencing in combination with conventional chemotherapeutic drugs on cell viability and major signaling pathways have not yet been fully investigated in breast cancer cells. In this study, we investigated the cytotoxic effects of Bag-1 silencing, alone and in combination with cisplatin or paclitaxel treatment, in MCF-7 breast cancer cells. Bag-1 knockdown by shRNA or siRNA transfection sensitized MCF-7 cells to apoptosis induced by cisplatin or paclitaxel. Combination of Bag-1 silencing and drug treatment more potently downregulated the pro-survival PI3K/Akt/mTOR and p44/42 mitogen activated protein kinase (MAPK) pathways, and more potently upregulated the stress-activated p38 and SAPK/JNK MAPK pathways. Bag1-silenced drug-treated cells had also highly reduced proliferative capacity, downregulated cyclin–cyclin dependent kinase complexes and upregulated tumor suppressors p21 and Rb. These results overall indicated that Bag-1 silencing enhanced cisplatin- or paclitaxel-induced cytotoxicity through multiple pathways. In conclusion, Bag-1 targeted therapy might enhance the therapeutic potential of conventional anti-cancer drugs in the treatment of breast cancer.
Embargo
Bag-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; 6125
Background: 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.
Embargo
Bag-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; 6125
Background: 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.
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Biological responses of ultrafine grained pure titanium and their sand blasted surfaces
(Elsevier Science Bv, Po Box 211, 1000 Ae Amsterdam, Netherlands, 2018-10-01) Günay Bulutsuz, Aslı; Berrak, Özge; Yeprem, H. Aygül; Arısan, Elif Damla; Yurci, Mehmet Emin; 173771; 122108; 113920; 9193
The use of materials as implants has become vital for determining optimal product design to enhance the needs of usage and longevity in body. Ultrafine grained pure titanium offers advanced mechanical properties for medical applications for most adequate materials meso/micro scaled dental implants. Besides advanced mechanical properties, increased surface properties also offers enhance biocompatibility. In this experimental study, the effects of bulk structure on surface modification by sand blasting for coarse-grained and ultrafine-grained (UFG) commercially pure titanium reported. To determine the effects of bulk structure on the polished and modified surfaces the specimen groups are investigated using Optic Microscope (OM), Electron Back Scattering Diffraction (EBSD) and Confocal Laser-Scanning Microscope (CLSM). Surface roughness is determined with stylus profilometer (SP) and CLSM. Understanding the biocompatibility of titanium surfaces to cell-cell interactions and cell proliferation capacity of attached-cells were determined by cell viability assays and fluorescence microscopy techniques. According to our results, the titanium surfaces were highly available to cell attachment and cell proliferation. The ratios of cell proliferation of cells which are attached on different titanium surfaces were dependent on the grain size and the surface roughness. UFG and blasted surfaces are more suitable for cell proliferation of human gingival fibroblast cells.

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