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Clinical Cancer Research Vol. 6, 916-923, March 2000
© 2000 American Association for Cancer Research

Experimental Therapeutics, Preclinical Pharmacology

p27Kip1 Accumulation by Inhibition of Proteasome Function Induces Apoptosis in Oral Squamous Cell Carcinoma Cells1

Yasusei Kudo2, Takashi Takata, Ikuko Ogawa, Toshihiko Kaneda, Sunao Sato, Toshitsugu Takekoshi, Ming Zhao, Mutsumi Miyauchi and Hiromasa Nikai

Department of Oral Pathology, Hiroshima University, Faculty of Dentistry [Y. K., T. T., T. K., S. S., T. T., M. Z., M. M., H. N.], and Clinical Laboratory, Hiroshima University Dental Hospital [I. O.], Hiroshima 734-8553, Japan

Ubiquitin-mediated proteolysis controls intracellular levels of various cell cycle regulatory proteins, and its inhibition has been shown to induce apoptosis in proliferating cells. In the present study, we examined induction of apo-ptosis in oral squamous cell carcinoma (OSCC) cells by treatment with specific proteasome inhibitors, carbobenzoxy-L-leucyl-L-leucyl-L-norvalinal and lactacystin. In all three OSCC cell lines examined, apoptotic changes such as apo-ptotic body formation and DNA fragmentation were observed at various degrees after 24 h of the carbobenzoxy-L-leucyl-L-leucyl-L-norvalinal or lactacystin treatment. HSC2 cells showed the most prominent apoptotic changes among the cell lines examined and demonstrated the highest level of accumulation of p27Kip1 protein after the treatment with proteasome inhibitor. Reduced expressions of cyclin D1 and phospho pRb were also observed after the treatment with proteasome inhibitor. Moreover, 12 h of treatment with the proteasome inhibitor inhibited cdk2/cyclin E kinase activity and increased the ratio of the cell cycle population at the G1 phase. The proteasome inhibitor led to inhibition of cell cycle progression. In addition, activation of CPP32 and reduced expression of Bcl-2 were observed. Because apo-ptosis induced by the proteasome inhibitor was inhibited by treatment with antisense p27Kip1 oligonucleotide, accumulation of the p27Kip1 protein might play an important role in the apoptosis induced by proteasome inhibitor. The present results suggest that inhibition of proteasome function may be used as a possible target of novel therapy for OSCC.




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