2-Methoxyestradiol induces endoreduplication through the induction of mitochondrial oxidative stress and the activation of MAPK signaling pathways
Publication in refereed journal



摘要2-Methoxyestradiol (2ME2) is a normal physiological metabolite of 17 beta-estradiol with anti-proliferative and anti-angiogenic activities. The purpose of this Study is to elucidate the mechanism whereby 2ME2 induces endoreduplication of the well-differentiated nasopharyngeal carcinoma (NPC) cells. We report here that 2ME2 induces G2/M phase cell cycle arrest followed by endoreduplication of the well-differentiated HK-1 cells. The increase in chromosome number was Confirmed by cytogenetic study. Analysis of stress signaling pathways revealed the phosphorylation activation of ERK, JNK and p38 MAPKs at various times after 2ME2 treatment. Pre-treatment of 2ME2-treated HK-1 cells with JNK inhibitor (SP600125), ERK inhibitor (PD98059) and p38 MAPK inhibitor (SB203580) resulted in the reduction of endoreduplicating cells. Furthermore, the increase in the phosphorylation of JNK was accompanied by an increase in the reactive oxygen species. In addition, endoreduplication was observed in cells after treatment with superoxide donor, 2,3-dimethoxy-1,4-napoquinone (DMNQ). Confocal microscopic analysis also revealed the increase in mitochondrial superoxide anion in 2ME2-treated HK-1 cells. Pre-treatment of HK-1 cells with superoxide dismutase mimetic 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) or overexpressing the mitochondrial enzyme MnSOD resulted in the reduction of phosphorylation of JNK and the formation of endoreduplicating cells. Furthermore, the tubulin filaments in cytoplasm remain intact in 2ME2-treated HK-1 cells after pre-treatment of TEMPO. Our results suggest that 2ME2 induces endoreduplication through the induction of oxidative stress and the activation of MAPK signal pathways. The biological significance of drug-induced endoreduplication will also be discussed. (C) 2009 Elsevier Inc. All rights reserved.
著者Ting CM, Lee YM, Wong CKC, Wong AS, Lung HL, Lung ML, Lo KW, Wong RNS, Mak NK
期刊名稱Biochemical Pharmacology
頁次825 - 841
關鍵詞2-Methoxyestradiol; Endoreduplication; MAPK signaling pathways; Mitochondria; Nasopharyngeal carcinoma; Oxidative stress
Web of Science 學科類別Pharmacology & Pharmacy; PHARMACOLOGY & PHARMACY

上次更新時間 2021-12-09 於 00:03