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Int J Cancer. 1998 Aug 12;77(4):578-85.

Involvement of proteasomes in migration and matrix metalloproteinase-9 production of oral squamous cell carcinoma.

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Second Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Kyushu University, Fukuoka, Japan.


We investigated whether proteasomes were involved in the invasiveness of oral squamous cell carcinoma (SCC) cells. The migration of SCC cells through a gelatin-coated membrane was enhanced with tumor necrosis factor alpha (TNF alpha), which was strongly inhibited by a peptide aldehyde, N-acetyl-Leu-Leu-norleucinal (ALLN), but not by its structurally related compound, N-acetyl-Leu-Leu-methioninal (ALLM). Since ALLN is a more potent inhibitor against proteasomal proteolysis than ALLM, cell migration inhibited by ALLN may thus likely depend on proteasomes. The TNF alpha-induced migration through gelatin appeared to be associated with the gelatinolytic activity from the cells, since TNF alpha strongly enhanced the production of matrix metalloproteinase (MMP)-9/gelatinase B in the SCC cells, as detected by gelatin zymography. The production of MMP-9 was also inhibited by pretreatment with ALLN, but not ALLM, in a dose-dependent manner. Moreover, ALLN could block the activation and nuclear translocation of a transcription-activating factor, NF-kappaB, which is known to regulate MMP-9 expression in TNF alpha-stimulated SCC cells. The TNF alpha-induced degradation of IkappaB alpha was also suppressed by ALLN treatment, thus implying that the molecule linking proteasome to MMP-9 production should be IkappaB alpha. We finally reconfirmed the involvement of proteasomes in the invasive behavior of oral SCC using lactacystin, a specific proteasome inhibitor, which could prevent TNF alpha from enhancing MMP-9 production, NF-kappaB activation, induction of MMP-9 mRNA and cell migration.

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