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

  • Authors:
    • Jo Ishizawa
    • Shuichi Yoshida
    • Mototsugu Oya
    • Ryuichi Mizuno
    • Toshiaki Shinojima
    • Ken Marumo
    • Masaru Murai
  • View Affiliations

  • Published online on: September 1, 2004     https://doi.org/10.3892/ijo.25.3.697
  • Pages: 697-702
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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.

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September 2004
Volume 25 Issue 3

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Ishizawa J, Yoshida S, Oya M, Mizuno R, Shinojima T, Marumo K and Murai M: Inhibition of the ubiquitin-proteasome pathway activates stress kinases and induces apoptosis in renal cancer cells. Int J Oncol 25: 697-702, 2004
APA
Ishizawa, J., Yoshida, S., Oya, M., Mizuno, R., Shinojima, T., Marumo, K., & Murai, M. (2004). Inhibition of the ubiquitin-proteasome pathway activates stress kinases and induces apoptosis in renal cancer cells. International Journal of Oncology, 25, 697-702. https://doi.org/10.3892/ijo.25.3.697
MLA
Ishizawa, J., Yoshida, S., Oya, M., Mizuno, R., Shinojima, T., Marumo, K., Murai, M."Inhibition of the ubiquitin-proteasome pathway activates stress kinases and induces apoptosis in renal cancer cells". International Journal of Oncology 25.3 (2004): 697-702.
Chicago
Ishizawa, J., Yoshida, S., Oya, M., Mizuno, R., Shinojima, T., Marumo, K., Murai, M."Inhibition of the ubiquitin-proteasome pathway activates stress kinases and induces apoptosis in renal cancer cells". International Journal of Oncology 25, no. 3 (2004): 697-702. https://doi.org/10.3892/ijo.25.3.697