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

Choi Man Ting, Yee Man Lee, Chris K C WONG, A. S. Wong, Hong Lok LUNG, M. L. Lung, K. W. Lo, Ricky N S WONG, Nai Ki MAK*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

Abstract

2-Methoxyestradiol (2ME2) is a normal physiological metabolite of 17β-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-naphoquinone (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.

Original languageEnglish
Pages (from-to)825-841
Number of pages17
JournalBiochemical Pharmacology
Volume79
Issue number6
DOIs
Publication statusPublished - 15 Mar 2010

Scopus Subject Areas

  • Biochemistry
  • Pharmacology

User-Defined Keywords

  • 2-Methoxyestradiol
  • Endoreduplication
  • MAPK signaling pathways
  • Mitochondria
  • Nasopharyngeal carcinoma
  • Oxidative stress

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