Down-regulation of trypsinogen-2 expression by chemically modified tetracyclines: association with reduced cancer cell migration.
Many types of human tumor express trypsinogen-2, which may be a significant factor in the activation of pro-MMPs and the invasiveness of tumors. Prevention of trypsinogen-2 expression in cancer cells might be of benefit in cancer therapy. We describe here chemicals capable of down-regulating the expression of trypsinogen-2. Doxycycline (DOXY) and chemically modified tetracyclines (CMTs), previously known as inhibitors of the matrix metalloproteinase (MMP)-dependent proteinase cascade, down-regulated the mRNA and protein expression of trypsinogen-2 by COLO-205 human colon adenocarcinoma cells at therapeutically attainable concentrations (0. 1 to 1.0 microM). DOXY specifically inhibited the activation of pro-MMP-9 and cell migration induced by enteropeptidase, a specific activator of trypsinogen. Pro-MMP-9 activation and cell migration were also inhibited by tumor-associated trypsin inhibitor (TATI), which is a highly specific inhibitor of trypsin. CMT-3 as well as CMT-5 also inhibited cell migration, but an effect on the enteropeptidase-enhanced activation of pro-MMP-9 was not observed. Our results indicate that CMTs, DOXY and TATI inhibit cancer cell migration by down-regulating trypsinogen-2 expression or activity. Inhibition of trypsinogen-2 expression may represent a mechanism contributing to the ability of CMTs to suppress the pericellular proteolytic activity of some tumors.
Lukkonen
A
A
Department of Clinical Chemistry, Helsinki University Central Hospital, Helsinki, Finland. annukka.lukkonen@helsinki.fi
Sorsa
T
T
Salo
T
T
Tervahartiala
T
T
Koivunen
E
E
Golub
L
L
Simon
S
S
Stenman
U H
UH
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D015536:Down-Regulation; D004792:Enzyme Precursors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D013754:Tetracyclines / Q000494:pharmacology*; D014357:Trypsin; D014361:Trypsin Inhibitors / Q000494:pharmacology; D014362:Trypsinogen / Q000037:antagonists & inhibitors* / Q000235:genetics; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004792:Enzyme Precursors; D013754:Tetracyclines; D014361:Trypsin Inhibitors; C064831:PRSS2 protein, human; D014362:Trypsinogen; D014357:Trypsin; D020780:Matrix Metalloproteinase 9