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

Int J Cancer. 1998 Aug 12;77(4):578-85. doi: 10.1002/(sici)1097-0215(19980812)77:4<578::aid-ijc18>;2-2.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / pathology*
  • Collagenases / metabolism*
  • Cysteine Proteinase Inhibitors / pharmacology
  • Gelatinases / metabolism
  • Humans
  • Leupeptins / pharmacology
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • Matrix Metalloproteinase Inhibitors
  • Metalloendopeptidases / metabolism
  • Mouth Neoplasms / metabolism*
  • Mouth Neoplasms / pathology*
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Neoplasm Invasiveness
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / metabolism*
  • Oligopeptides / pharmacology
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / pharmacology


  • Cysteine Proteinase Inhibitors
  • Leupeptins
  • Matrix Metalloproteinase Inhibitors
  • NF-kappa B
  • Neoplasm Proteins
  • Oligopeptides
  • Tumor Necrosis Factor-alpha
  • acetylleucyl-leucyl-norleucinal
  • calpain inhibitor 2
  • Collagenases
  • Gelatinases
  • Metalloendopeptidases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9