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 journalArticle

24 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

Fingerprint

Dual Specificity Phosphatase 1
Renal Cell Carcinoma
Phosphotransferases
Apoptosis
Anisomycin
Extracellular Signal-Regulated MAP Kinases
p38 Mitogen-Activated Protein Kinases
Cell Line
Mitogen-Activated Protein Kinase Phosphatases
Mitogen-Activated Protein Kinase 3
JNK Mitogen-Activated Protein Kinases
Kidney Neoplasms
In Situ Nick-End Labeling
DNA Fragmentation
Protein Kinases
Cell Survival
Western Blotting
Ro 31-8220

Keywords

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

ASJC Scopus subject areas

  • Urology

Cite this

Inhibition of MKP-1 expression potentiates JNK related apoptosis in renal cancer cells. / Mizuno, Ryuichi; Oya, Mototsugu; Shiomi, Takayuki; Marumo, Ken; Okada, Yasunori; Murai, Masaru.

In: Journal of Urology, Vol. 172, No. 2, 08.2004, p. 723-727.

Research output: Contribution to journalArticle

Mizuno, Ryuichi ; Oya, Mototsugu ; Shiomi, Takayuki ; Marumo, Ken ; Okada, Yasunori ; Murai, Masaru. / Inhibition of MKP-1 expression potentiates JNK related apoptosis in renal cancer cells. In: Journal of Urology. 2004 ; Vol. 172, No. 2. pp. 723-727.
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AU - Mizuno, Ryuichi

AU - Oya, Mototsugu

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AU - Okada, Yasunori

AU - Murai, Masaru

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N2 - 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.

AB - 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.

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