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    Decreased Expression of HN1 Sensitizes Prostate Cancer Cells to Apoptosis Induced by Docetaxel and 2-Methoxyestradiol
    (Assoc Clinical Scientists, 2022) Varisli, Lokman
    Objective. Prostate cancer is one of the most frequently diagnosed cancer in men and ranks as the second most common cause of cancer-related deaths in developed countries. HN1 is a highly expressed gene in prostate cancer and controls the levels of several cell cycle regulatory proteins including Cyclin B1. Cyclin B1 is a cell cycle control protein but is also involved in Docetaxel and 2-Methoxyestradiol induced apoptosis. Since Cyclin B1 level may affect chemotherapy success and HN1-Cyclin B1 negative correlation has already been shown, so in this study, we investigated the possible role of HN1 in chemotherapeutic resistance in prostate cancer cells. Methods. Androgen-dependent and independent prostate cancer cells were used in the study. A full-length human HN1 cDNA fragment was cloned to a mammalian expression vector and this construct was used for overexpression experiments. A siRNA that specifically targets HN1 was used for HN1 depletion experiments. Evaluation of apoptosis was performed by the level of PARP cleavage and an apoptosis kit that measure Caspase 3 activity. Results. The HN1 protein level is decreased in the Docetaxel or 2-Methoxyestradiol treated LNCaP and PC-3 PCa cells whereas the Cyclin B1 level is increased. HN1 overexpression inhibited Docetaxel and 2-Methoxyestradiol induced apoptosis. In concordance, its depletion further stimulated apoptosis in drug-treated cells. However, silencing of Cyclin B1 along with HN1 abolished the increased apoptotic response induced by silencing of HN1 in Docetaxel or 2-Methoxyestradiol treated cells. Conclusion. HN1 is an anti-apoptotic molecule and inhibits Docetaxel and 2-Methoxyestradiol induced apoptosis by targeting Cyclin B1.
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    Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways
    (IMMUA, 2020) Varisli, Lokman; Cen, Osman; Vlahopoulos, Spiros
    Chloroquines are 4-aminoquinoline-based drugs mainly used to treat malaria. At pharmacological concentrations, they have significant effects on tissue homeostasis, targeting diverse signaling pathways in mammalian cells. A key target pathway is autophagy, which regulates macromolecule turnover in the cell. In addition to affecting cellular metabolism and bioenergetic flow equilibrium, autophagy plays a pivotal role at the interface between inflammation and cancer progression. Chloroquines consequently have critical effects in tissue metabolic activity and importantly, in key functions of the immune system. In this article, we will review the work addressing the role of chloroquines in the homeostasis of mammalian tissue, and the potential strengths and weaknesses concerning their use in cancer therapy.
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    Increased ROS alters E-/N-cadherin levels and promotes migration in prostate cancer cells
    (Aepress, 2022) Varisli, Lokman; Tolan, Veysel
    Background: Increased ROS has been reported to cause a change in E- and N-cadherin levels, and consequently promotes migrative behaviors in pancreas and breast cancer cells. In this study, the effect of a sublethal dose of H2O2 on E- and N-cadherin levels, and on migrative behaviors of PCa cells was investigated. Methods: To determine a sublethal concentration of H2O2 on cell proliferation and ROS production were examined using WST-1 and DCFH-DA assays, respectively. E- and N-cadherin protein and mRNA levels were investigated by western blotting and real-time PCR, respectively. The migrative potentials of the cells were examined by Cytoselect 96-well cell migration assay. Results: Treatment of the PCa cells with a sublethal dose of H2O2 results in a decrease in E-cadherin and an increase in N-cadherin levels, at both mRNA and protein levels. However, inhibition of ERK using PD98059 abolishes the effects of H2O2. In addition, the cells that were treated with H2O2 have gained further migrative abilities compared to control cells, and this ability was repressed when PD98059 was used together with H2O2. Conclusion: Increased ROS alters E- and N-cadherin levels in an ERK-dependent manner and thereby promotes the migrative abilities of PCa cells.