MISC

2006年12月

Lymphokine-activated killer T-cell-originated protein kinase. Phosphorylation of histone H2AX prevents arsenite-induced apoptosis in RPMI7951 melanoma cells

CLINICAL CANCER RESEARCH
  • Tatyana A. Zykova
  • ,
  • Feng Zhu
  • ,
  • Chengrong Lu
  • ,
  • LeeAnn Higgins
  • ,
  • Yasuaki Tatsumi
  • ,
  • Yasuhito Abe
  • ,
  • Ann M. Bode
  • ,
  • Zigang Dong

12
23
開始ページ
6884
終了ページ
6893
記述言語
英語
掲載種別
DOI
10.1158/1078-0432.CCR-06-0410
出版者・発行元
AMER ASSOC CANCER RESEARCH

Purpose: Arsenic is a valuable therapeutic tool in cancer treatment. Lymphokine-activated killer T-cell-originated protein kinase (TOPK) is highly expressed in cancer cells, but its specific function is still unknown. We investigated the role of TOPK in arsenic-induced apoptosis in RPMI7951 human melanoma cells.
Experimental Design: Expression of TOPK was evaluated in different melanoma cell lines, and liquid chromatography-tandem mass spectrometry analysis was used to identify proteins binding with TOPK. Immunofluorescence, Western blot, and flow cytometry were used to assess the effect of arsenic on TOPK, histone H2AX, and apoptosis in RPMI7951 cells.
Results: Melanoma cell lines expressing high levels of TOPK were more resistant to arsenite (As3+)-induced apoptosis. As3+ treatment induced phosphorylation of TOPK and histone H2AX in RPMI7951 human melanoma cells. Liquid chromatography-tandem mass spectrometry results indicated that TOPK could bind with histone H2AX, and in vitro and in vivo assays confirmed that TOPK binds with and phosphorylates histone H2AX. As3+ treatment caused phosphorylation of TOPK, which colocalized with phosphorylated histone H2AX in the nucleus. TOPK small interfering RNA cells exhibited a decreased phosphorylation of histone H2AX with As3+ treatment. As3+-induced apoptosis was decreased in H2AX(-/-) cells but increased in TOPK small interfering RNA cells.
Conclusions: TOPK binds with histone H2AX and inhibits As3+-induced apoptosis through phosphorylation of histone H2AX. Melanoma cell lines with high levels of TOPK are more resistant to As3+-induced apoptosis. Therefore, inhibition of TOPK activity combined with As3+ treatment may be helpful in the treatment of melanomas.

Web of Science ® 被引用回数 : 51

リンク情報
DOI
https://doi.org/10.1158/1078-0432.CCR-06-0410
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000242691000004&DestApp=WOS_CPL