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NGUYEN THANH THANH QUE Graduate School Gachon University 2020 국내석사
ABSTRACT Synergistic anti-proliferation effects of all-trans retinoic acid with paclitaxel on autosomal polycystic kidney disease cell line. Que Thanh Thanh Nguyen Supervisor: Prof. Jae Young Kim Department of Life Science Graduate School of Gachon University Autosomal dominant polycystic kidney disease (ADPKD) has been well-known as a monogenic inherited disorder and characterized by cyst development in the kidney. In recent years, the mechanism in autosomal dominant polycystic kidney disease (ADPKD) associated to genetic factors and non-genetic factors have been widely studied to get deep knowledge about ADPKD. In renal tubules, renal epithelial cells over-growth due to lower intracellular calcium level and the mitogenic effect of cAMP (cyclic adenosine monophosphate), is one of the hallmark features that originated cystogenesis. In this study, for the first time, we investigated the synergistic effects of combinatory treatment between all-trans retinoic acid (ATRA), an active form of vitamin A, and paclitaxel, a high effective anticancer drug, on the autosomal dominant polycystic kidney cell line. Cells were treated with a combination of ATRA with paclitaxel for 48 h and then analyzed by cell viability assay. In combinatory treatment groups, our data indicated that the percentage of cell viability was significantly decreased in the comparison with DMSO (control) and ATRA/paclitaxel (alone) treatment. Cell cycle arrest showed that the combinatory treatment of ATRA with paclitaxel induce ADPKD cell line arrest at the G2/M phase. Furthermore, apoptotic cells were detected in our study by Annexin V/PI staining. The up-regulation of p53 protein expression and caspase activation could be involved in apoptosis signal and cell cycle arrest. We revealed that the intra-calcium level was sharply increased by combined treatment of ATRA and paclitaxel after 72 h of treatment and this enhance was blocked by RARα/RXRα antagonist or calcium channel blockers. Besides, ADPKD cell proliferation was controlled through the ERK signaling pathway by in phosphorylated ERK. Our result suggested the function of combinatorial treatment of ATRA with paclitaxel which expresses synergistic anti-proliferation effect on ADPKD cell proliferation by inducing cell cycle arresting, apoptosis and suppressing the ERK signaling pathway. Keywords: Autosomal polycystic kidney disease (ADPKD), ATRA, paclitaxel, cell cycle arrest, apoptosis, intracellular calcium, phosphorylated ERK1/2.