Inhibition of MKP-1 expression potentiates JNK related apoptosis in renal cancer cells

Ryuichi Mizuno, Mototsugu Oya, Takayuki Shiomi, Ken Marumo, Yasunori Okada, Masaru Murai

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

Abstract

Purpose: Mitogen-activated protein kinases (MAPKs) comprise 3 subgroups, that is extracellular signal-regulated protein kinase, c-Jun N-terminal kinase (JNK) and p38 MAPK (p38). In this study we analyzed the role of JNK as well as the expression of MAPK phosphatase-1 (MKP-1) in renal cancers. Materials and Methods: Four renal cell carcinoma (RCC) cell lines were used. The effects of anisomycin (JNK activator) and Ro-318220 (MKP-1 expression inhibitor) were analyzed by alamar blue assay. Apoptosis was determined by flow cytometric TUNEL analysis, nuclear morphological alternations and the detection of DNA fragmentation. Changes in MKP-1 expression as well as the activation of extracellular signal-regulated protein kinases and JNK were analyzed by Western blotting. Results: All cell lines treated with anisomycin resulted in a transient activation of JNK without inducing apoptosis. Since we hypothesized that elevated MKP-1 expression could possibly prevent persistent JNK activation, Ro-318220 was used. When cells were treated with Ro-318220, MKP-1 expression decreased in Caki-1 and KU 20-01 cells but not in ACHN or 769P cells. Combined treatment of Caki-1 and KU 20-01 cells with anisomycin and Ro-318220 resulted in a decrease in MKP-1 expression concomitant with persistent JNK activation. Apoptosis was induced in each cell line. Conclusions: These results suggest that prevalent MKP-1 expression in RCC contributes to cancer cell survival by attenuating an apoptosis inducing signal cascade via JNK. Since Ro-318220 potentiated JNK related apoptosis, JNK activation by blocking MKP-1 expression may be an effective therapeutic approach to RCC.

Original languageEnglish
Pages (from-to)723-727
Number of pages5
JournalJournal of Urology
Volume172
Issue number2
DOIs
Publication statusPublished - 2004 Aug

Keywords

  • Apoptosis
  • Carcinoma, renal cell
  • JNK mitogen-activated protein kinases
  • Kidney
  • Mitogen activated protein kinases

ASJC Scopus subject areas

  • Urology

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