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Down‐regulation of trypsinogen‐2 expression by chemically modified tetracyclines: Association with reduced cancer cell migration
Author(s) -
Lukkonen Annukka,
Sorsa Timo,
Salo Tuula,
Tervahartiala Taina,
Koivunen Erkki,
Golub Lorne,
Simon Sanford,
Stenman UlfHåkan
Publication year - 2000
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(20000515)86:4<577::aid-ijc21>3.0.co;2-j
Subject(s) - trypsinogen , enteropeptidase , matrix metalloproteinase , trypsin , cancer research , cancer cell , pancreatic cancer , cell migration , cell , chemistry , biology , cell growth , cancer , microbiology and biotechnology , biochemistry , enzyme , gene , genetics , fusion protein , recombinant dna
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 μM). 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. Int. J. Cancer 86:577–581, 2000. © 2000 Wiley‐Liss, Inc.