Mechanisms of 2-methoxyestradiol-induced apoptosis and G2/M cell-cycle arrest of nasopharyngeal carcinoma cells

Yee Man Lee, Choi Man Ting, Yuen Kit CHENG, Tai Ping Fan, Ricky N S WONG, Maria Li Lung, Nai Ki MAK*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Citations (Scopus)

Abstract

2-Methoxyestradiol (2ME2) is an endogenous metabolite of 17β-estradiol (E2). This study aims to examine the anti-tumour activities of 2ME2 on the poorly differentiated HONE-1 NPC cell line. At the concentration of 1 μM, 2ME2 was found to induce a short-term reversible G2/M cell-cycle arrest. Further 10-fold increase to 10 μM, 2ME2 induced both irreversible G2/M phase cell-cycle arrest and apoptosis. Induction of apoptosis and G2/M cell-cycle arrest was due to oxidative stress as both apoptosis and the proportion of cells arresting at G2/M phase could be reduced by the superoxide dismutase (SOD) mimetic, TEMPO. Induction of apoptosis was accompanied with proteolytic cleavage of caspase-9 and -3, but not caspase-8. Kinetics studies revealed that 2ME2 induced a time-dependent inhibition of extracellular signal-regulated protein kinase (ERK) and an activation of c-jun N-terminal kinases (JNKs). The chemical inhibitor of JNKs, SP600125, was found to reduce 2ME2-induced apoptosis of the HONE-1 cells. Confocal microscopy revealed that the induction of G2/M cell-cycle arrest was associated with the presence of immunoreactivity of p-cdc2 (Tyr15) in the nucleus. The G2/M cell-cycle arrest is also correlated with an increased level of inactive p-cdc25C (Ser216) in 2ME2-treated HONE-1 cells. Results from this study indicate that production of superoxide anions might be involved in 2ME2-induced apoptosis and G2/M cell-cycle arrest of the HONE-1 cells.

Original languageEnglish
Pages (from-to)295-307
Number of pages13
JournalCancer Letters
Volume268
Issue number2
DOIs
Publication statusPublished - 18 Sep 2008

Scopus Subject Areas

  • Oncology
  • Cancer Research

User-Defined Keywords

  • 2-Methoxyestradiol
  • Apoptosis
  • Cell-cycle arrest
  • Nasopharyngeal carcinoma

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