Inhibition of the ubiquitin-proteasome pathway activates stress kinases and induces apoptosis in renal cancer cells.

J. Ishizawa, Shuichi Yoshida, Mototsugu Oya, Ryuichi Mizuno, Toshiaki Shinojima, Ken Marumo, Masaru Murai

Research output: Contribution to journalArticle

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Abstract

The ubiquitin-proteasome pathway plays a critical role in the degradation of cellular proteins related to signal transduction. Cytokine and growth factor-dependent aberrant proliferation has been implicated in renal cell carcinoma (RCC). We hypothesized that inhibiting the proteasome function might activate a proapoptotic signal transduction by modulating the cytokine and growth factor related signal transduction pathway. We therefore investigated the effectiveness of a proteasome inhibitor in the treatment of RCC regarding the involvement of Mitogen-activated protein kinases (MAP kinases), because MAP kinases are major signal transduction molecules that are known to play a pivotal role in cancer cell proliferation or apoptosis triggered by extra-cellular cytokines and growth factors. A proteasome inhibitor, MG132 inhibited the proliferation of RCC cell lines, 786-O and KU20-01 in a time and dose-dependent manner. 786-O cells have truncated von-Hippel Lindau (VHL) tumor suppressor gene protein due to a one base pair deletion at exon 1, whereas KU20-01 cells have a wild-type VHL protein. MG132 induced apoptosis in both cell lines. The inhibition of the ubiquitin-proteasome pathways was confirmed by the accumulation of ubiquitin-tagged proteins. MG132 induced the phosphorylation of ERK at 4 h and thereafter persisted for 8 to 16 h. In contrast, JNK and p38 activation persisted for longer periods and remained enhanced until 24 h. The concomitant activation of effector caspases, caspase-3 and caspase-7 was observed in 786-O cells. The inhibition of the proteasome function can induce apoptosis in RCC irrespective of the VHL protein status. The persistence of JNK and p38 activation may therefore be a unique mechanism underlying MG132 induced apoptosis.

Original languageEnglish
Pages (from-to)697-702
Number of pages6
JournalInternational Journal of Oncology
Volume25
Issue number3
Publication statusPublished - 2004 Sep

Fingerprint

Proteasome Endopeptidase Complex
Ubiquitin
Renal Cell Carcinoma
Signal Transduction
Phosphotransferases
Apoptosis
Intercellular Signaling Peptides and Proteins
Proteasome Inhibitors
Cytokines
Mitogen-Activated Protein Kinases
Von Hippel-Lindau Tumor Suppressor Protein
Proteins
Effector Caspases
Caspase 7
Cell Line
Tumor Suppressor Genes
Base Pairing
Caspase 3
Proteolysis
Exons

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Inhibition of the ubiquitin-proteasome pathway activates stress kinases and induces apoptosis in renal cancer cells. / Ishizawa, J.; Yoshida, Shuichi; Oya, Mototsugu; Mizuno, Ryuichi; Shinojima, Toshiaki; Marumo, Ken; Murai, Masaru.

In: International Journal of Oncology, Vol. 25, No. 3, 09.2004, p. 697-702.

Research output: Contribution to journalArticle

Ishizawa, J. ; Yoshida, Shuichi ; Oya, Mototsugu ; Mizuno, Ryuichi ; Shinojima, Toshiaki ; Marumo, Ken ; Murai, Masaru. / Inhibition of the ubiquitin-proteasome pathway activates stress kinases and induces apoptosis in renal cancer cells. In: International Journal of Oncology. 2004 ; Vol. 25, No. 3. pp. 697-702.
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