Preparing your results

Our searching services are busy right now. Your search will reload in five seconds.

X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

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

http://www.ncbi.nlm.nih.gov/pubmed/17145805

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 (As(3+))-induced apoptosis. As(3+) 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. As(3+) 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 As(3+) treatment. As(3+)-induced apoptosis was decreased in H2AX(-/-) cells but increased in TOPK small interfering RNA cells. CONCLUSIONS: TOPK binds with histone H2AX and inhibits As(3+)-induced apoptosis through phosphorylation of histone H2AX. Melanoma cell lines with high levels of TOPK are more resistant to As(3+)-induced apoptosis. Therefore, inhibition of TOPK activity combined with As(3+) treatment may be helpful in the treatment of melanomas.

Pubmed ID: 17145805 RIS Download

Mesh terms: Animals | Apoptosis | Arsenites | Cell Line, Tumor | Chromatography, Liquid | Dose-Response Relationship, Drug | Histones | Humans | Killer Cells, Lymphokine-Activated | Mass Spectrometry | Melanoma | Mice | Mitogen-Activated Protein Kinase Kinases | Phosphorylation | Protein Binding | Protein-Serine-Threonine Kinases | RNA, Small Interfering | Structure-Activity Relationship

Research resources used in this publication

None found

Research tools detected in this publication

None found

Data used in this publication

None found

Associated grants

  • Agency: NCI NIH HHS, Id: CA111356
  • Agency: NCI NIH HHS, Id: CA111536
  • Agency: NCI NIH HHS, Id: CA77646
  • Agency: NCI NIH HHS, Id: R01 CA077646
  • Agency: NCI NIH HHS, Id: R01 CA077646-05
  • Agency: NCI NIH HHS, Id: R01 CA111356
  • Agency: NCI NIH HHS, Id: R01 CA111356-01
  • Agency: NCI NIH HHS, Id: R01 CA111536
  • Agency: NCI NIH HHS, Id: R01 CA111536-01A1

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.