Master Degree / Yüksek Lisans Tezleri

Permanent URI for this collectionhttps://hdl.handle.net/11147/3008

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2009 - 20103

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Author: search.filters.author.Baran, YusufSubject: search.filters.subject.Ceramides

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Now showing 1 - 3 of 3
  • Master Thesis
    The Involvement of Ceramide Metabolizing Genes and Their Products in Docetaxel Induced Apoptosis in Human Prostate Cancer Cells
    (Izmir Institute of Technology, 2009) Başsoy, Esen Yonca; Baran, Yusuf
    Patients diagnosed with prostate cancer initially respond to androgen ablation therapy with tumor cells undergoing apoptosis, but then the patients relapse in time and develop metastatic, androgen independent prostate cancer. Docetaxel has been widely used for treatment of patients with advanced metastatic prostate cancer. The sphingolipid, ceramide, is a lipid second messenger that mediates a lot of functions as regulation of cell growth, proliferation, differentiation, senescence and apoptotic responses in various cancer cells. The enzyme, glucosylceramide synthase (GCS) is responsible for bioactivation of the proapoptotic mediator ceramide to antiapoptotic glucosylceramide. Likewise, sphingosine kinase-1 (SK-1) transforms apoptotic ceramide to antiapoptotic sphingosine 1-phosphate. Emerging results indicate that GCS and SK-1 are overexpressed in resistant cancer cell lines and cancerous tissue samples of patients. Moreover apoptosis and inhibition of cell proliferation and survival are induced by intracellular ceramide levels including enhancement in de novo ceramide production, exogenous delivery of cell permeable ceramide and inhibition of ceramide metabolism by affecting GCS and SK-1. In this study, we applied exogenous ceramide and inhibitors of GCS and SK-1 in combination with docetaxel for sensitizing androgen independent prostate cancer cells to chemotherapy and provide their effectively utilization with minimizing side effects of the drugs. The de novo generation of ceramide is regulated by the genes (LASS1-6) in mammalian cells. Therefore in this study, we examined the possible roles of the ceramide/S1P and ceramide/GS by examining expression levels of GCS, SK-1 and LASS1,2,4,5,6 which can play important roles to overcome androgen independent.
  • Master Thesis
    Activated Signaling Pathways and Apoptotic Mechanisms in Resveratrol Applied Chronic Myeloid Leukemia Cells and the Involvement of Ceramide Metabolizing Genes on These Mechanisms
    (Izmir Institute of Technology, 2010) Kartal Yandım, Melis; Baran, Yusuf; Baran, Yusuf
    Resveratrol, an important phytoalexin in many plants, has cytotoxic effects on several cancer cells. Ceramide is a significant sphingolipid which affects many signaling pathways regulating cell senescence, migration, and cell cycle arrest. Intracellular ceramide level is balanced by glucosylceramide synthase (GCS), the converter of ceramide to glucosylceramide, and sphingosine kinase-1 (SK-1) that convert ceramide to sphingosine 1-phosphate (S1P). Ceramide functions as an apoptotic molecule whereas glucosylceramide S1P function as anti-apoptotic. An important cell-permeable analogue of natural ceramides, C8:ceramide, increases intracellular ceramide levels significantly, while 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) and SK-1 inhibitor increase accumulation of ceramides by inhibiting GCS and SK-1, respectively. Chronic myelogenous leukemia (CML), a hematological disorder, results from the generation of BCR/ABL oncogene. In this study, we examined the roles of ceramide metabolizing genes in resveratrol-induced apoptosis, and the expression profiles of 84 genes underlying apoptosis, cell cycle control, DNA damage repair, and invasion and metastasis in human K562 CML cells treated with resveratrol. There were synergistic cytotoxic and apoptotic effects of resveratrol with coadministration of C8:ceramide, PDMP and SK-1 inhibitor. We observed significant increases in expression levels of LASS genes, and decreases in expression levels of GCS and SK-1 in K562 cells in response to increasing concentrations of resveratrol. There were also significant increases in the expression levels of SERPINB5, FAS, TNFRSF, MTSS that are related with tumor suppression, and decreases in Myc expression. Our data, in total, showed for the first time that resveratrol might kill CML cells through increasing intracellular generation and accumulation of apoptotic ceramides.
  • Master Thesis
    The Roles of Ceramide Metabolizing Gennes on Resveratrol Induced Apoptosis in Human Hl60 Acute Myeloid Leukemia Cells
    (Izmir Institute of Technology, 2010) Çakır, Zeynep; Baran, Yusuf
    Resveratrol (3,5,4' -trihydroxy-trans-stilbene) is naturally occurring phytoalexin, which presents especially in grapes. It is a potential anticancer agent which inhibits tumor initiation, promotion, and progression. Ceramides are the central compounds of sphingolipids metabolism. They are known as second messengers regulating various cellular processes including cell growth, proliferation, differentiation and apoptosis. While ceramide acts as a strong apoptotic molecule, glucosylceramide (GluCer) and sphingosine-1-phosphate (S1P) trigger cell growth and proliferation and inhibit apoptosis. Sphingosine kinase-1 (SK-1) is an enzyme catalyzing the phosphorylation of sphingosine to sphingosine-1-phosphate while glucosylceramide synthase (GCS) converts ceramide to glucosylceramide. Thus, inhibition of GCS by N-(2-hydroxy-1-(4-morpholinylmethyl)-2-phenylethyl)-decanamide, hydrochloride (PDMP) or SK-1 by sphingosine kinase-1 inhibitor, or exogenous application of ceramide analog (C8:ceramide) results in increased accumulation of ceramides. The aim of the study is to examine the roles of ceramide, glucosylceramide and sphingosine-1-phosphate in resveratrol induced apoptosis in HL60 cells. In this study, it was demonstrated cytotoxic effects of resveratrol on human acute myeloid leukemia cells in addition to identify a novel mechanism of resveratrol-induced apoptosis by targeting ceramide metabolism. And also it was shown that via targeting ceramide-generating and/or ceramide-clearance genes provided ceramide generation and/or accumulation in response to resveratrol treatment. This study showed for the first time that there were significant induction of apoptosis through increasing intracellular concentrations of ceramides in resveratrol treated HL60 cell. Taking together all these results showed that ceramides may be involved in resveratrol-induced apoptosis.