Molecular Biology and Genetics / Moleküler Biyoloji ve Genetik
Permanent URI for this collectionhttps://hdl.handle.net/11147/9
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Article Citation - WoS: 44Citation - Scopus: 42Inflammation-Mediated Abrogation of Androgen Signaling: an in Vitro Model of Prostate Cell Inflammation(John Wiley and Sons Inc., 2014) Debeleç Bütüner, Bilge; Alapınar, Cansu; Varışlı, Lokman; Erbaykent Tepedelen, Burcu; Hamid, Syed Muhammad; Gönen Korkmaz, Ceren; Korkmaz, Kemal SamiAs 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 (TNFα, IL-6, and IL1β) in conditioned media (CM) were analyzed. Prostate cells were then fed with CM containing varying concentrations of TNFα, and IkB degradation, nuclear factor kappa B (NFκB) 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-TNFα 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.Article Citation - WoS: 12Citation - Scopus: 12Decreased Expression of Efs Is Correlated With the Advanced Prostate Cancer(SAGE Publications Inc., 2015) Sertkaya, Selda; Hamid, Syed Muhammad; Dilsiz, Nihat; Varışlı, LokmanProstate cancer is the most frequently diagnosed malignant neoplasm in men in the developed countries. Although the progression of prostate cancer and the processes of invasion and metastasis by tumor cells are comparatively well understood, the genes involved in these processes are not fully determined. Therefore, a common area of research interest is the identification of novel molecules that are involved in these processes. In the present study, we have used in silico and experimental approaches to compare the expression of embryonal Fyn-associated substrate (EFS) between normal prostate and prostate cancer. We showed that EFS expression is remarkably downregulated in prostate cancer cells, compared to normal prostate cells. We also found that decreased expression of EFS in prostate cancer cells is due to DNA methylation. In addition, we showed that high EFS expression is important to suppress a malignant behavior of prostate cancer cells. Therefore, we suggest that EFS should be considered as a novel tumor suppressor gene in prostate cancer.Article Citation - WoS: 8Citation - Scopus: 10Bioactive Sphingolipids in Docetaxel-Induced Apoptosis in Human Prostate Cancer Cells(Elsevier Ltd., 2012) Başsoy, Esen Yonca; Baran, YusufIn this study, we examined the possible roles of ceramide/sphingosine-1-phosphate and ceramide/glucosyleceramide signaling in docetaxel-induced apoptosis by examining expression levels of the glucosyleceramide synthase and sphingosine kinase-1 and ceramide synthase gene family. As confirmed by isobologram analysis, docetaxel in combination with agents that increase intracellular ceramide levels increased the cytotoxic and apoptotic effects of docetaxel synergistically. More importantly, RT-PCR results revealed that expression levels of glucosyleceramide synthase and sphingosine kinase-1 were downregulated and ceramide synthase genes were upregulated in response to docetaxel. This study identifies mechanisms underlying the involvement of ceramide metabolizing genes in docetaxel-induced apoptosis in prostate cancer cells. © 2012 Elsevier Masson SAS.Article Citation - WoS: 38Citation - Scopus: 47Docetaxel/Zoledronic Acid Combination Triggers Apoptosis Synergistically Through Downregulating Antiapoptotic Bcl-2 Protein Level in Hormone-Refractory Prostate Cancer Cells(John Wiley and Sons Inc., 2009) Karabulut, B.; Erten, C.; Gül, M. K.; Cengiz, E.; Karaca, B.; Küçükzeybek, Y.; Görümlü, G.; Atmaca, H.; Uzunoğlu, S.; Şanlı, U. A.; Baran, Yusuf; Uslu, R.Docetaxel, a semi-synthetic taxane analogue, is used effectively in the treatment of metastatic prostate cancer. Zoledronic acid, the most potent member of bisphosphonates, has shown pleiotropic anti-tumoral effects on prostate cancer cells. We have explored the possible additive/synergistic effects and the apoptotic pathways induced by combination treatment of docetaxel and zoledronic acid in hormone and drug refractory, PC-3 and DU-145 prostate cancer cells. Combination of docetaxel and zoledronic acid synergistically inhibits cell growth in PC-3 and DU-145 cells. Moreover, this effect was due to downregulation of antiapoptotic protein Bcl-2 in PC-3 and DU-145 cells. In conclusion, docetaxel/zoledronic acid combination is potentially a novel and effective approach for the treatment of prostate cancer.Article Citation - WoS: 23Citation - Scopus: 24Proteasome Inhibitor Bortezomib Increases Radiation Sensitivity in Androgen Independent Human Prostate Cancer Cells(Elsevier Ltd., 2010) Göktaş, Serdar; Baran, Yusuf; Ural, Ali Uğur; Yazıcı, Sertaç; Aydur, Emin; Başal, Şeref; Avcu, Ferit; Pekel, Aysel; Dirican, Bahar; Beyzadeoğlu, MuratObjectives: To investigate the effects of a strong proteasome inhibitor, bortezomib alone or in combination with radiotherapy on androgen-independent DU145 human prostate cancer cells. Proteasomes play important roles in cell cycle, proliferation, apoptosis, angiogenesis, and cellular resistance to chemotherapy and radiotherapy. Methods: Increasing concentrations of bortezomib alone or in combination with radiation were applied to DU145 cells and IC50 values that inhibited cell growth by 50% were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium-bromide assay. Apoptosis was determined using annexin V staining by flow cytometry. mRNA levels of proapoptotic caspase-3 and antiapoptotic Bcl-2 genes were examined by reverse transcriptase polymerase chain reaction. Results: The IC50 value of bortezomib was found to be 28 μm although 400- and 800-cGy radiation decreased the cell proliferation by 14% and 28%, respectively. In 400- and 800-cGy radiation applied DU145 cells, IC50 value of bortezomib decreased to 23- and 12 μm, respectively. Exposure to 5 μm bortezomib for 48 hours caused apoptosis in 35% of the population whereas 800-cGy radiation resulted apoptosis in 14% of cells. However, 42% of DU145 cells that were exposed to 800 cGy and 5 μm bortezomib underwent apoptosis. Reverse transcriptase polymerase chain reaction results showed a significant decrease in mRNA levels of antiapoptotic Bcl-2 gene and an increase in proapoptotic caspase-3 gene expression in the combination group compared to control group. Conclusions: Bortezomib increases radiation sensitivity in androgen-independent human DU145 prostate cancer cells through inhibition of Bcl-2 and induction of caspase-3 genes. © 2010 Elsevier Inc. All rights reserved.