Carcinogenesis, Vol 18, 2093-2100, Copyright © 1997 by Oxford University Press
A Shoji, Y Sakamoto, T Tsuchiya, K Moriyama, T Kaneko, T Okubo, M Umeda and K Miyazaki
Tissue inhibitor of metalloproteinases-1 (TIMP-1), a natural inhibitor of
matrix metalloproteinases (MMPs), is known to inhibit invasion and
metastasis of tumor cells. In the present study we examined anti-tumor
promoter activity of TIMP-1 and its effect on in vitro cell transformation
using BALB/3T3 cells in low serum culture medium. In the dye transfer assay
the tumor promoter 12-O-tetradecanoylphorbol-13- acetate (TPA) continuously
blocked gap-junctional intercellular communication (GJIC) of BALB/3T3 cells
in confluent phase. TIMP-1 did not prevent transient inhibition of GJIC
induced by TPA, but it quickly restored the reduced GJIC level to the
control level. The recovery of GJIC was dependent on the concentration of
TIMP-1 from 1 to 1000 ng/ml. In an in vitro two-stage transformation assay
in which BALB/3T3 cells were treated with 0.5 microg/ml
N-metyl-N'-nitro-N-nitrosoguanidine as initiator and 100 ng/ml TPA as
promoter, TIMP-1 at concentrations > 10 ng/ml inhibited the focus
formation of transformed cells by approximately 60%. TIMP-2 and a synthetic
MMP inhibitor showed a similar inhibitory activity on in vitro cell
transformation. Furthermore, zymographyic analysis showed that TPA
treatment of BALB/3T3 cells induced secretion of gelatinase B and
stromelysin-1 into the culture medium. These results indicate that TIMP-1
and TIMP-2 have inhibitory activity on in vitro transformation of cells. It
seems likely that TPA-inducible MMPs are involved in carcinogenesis and
TIMPs have a protective role against carcinogenesis in vivo.
ARTICLES
Inhibition of tumor promoter activity toward mouse fibroblasts and their in vitro transformation by tissue inhibitor of metalloproteinases- 1 (TIMP-1)
Division of Cell Biology, Kihara Institute for Biological Research, Yokohama City University, Yokohama, Japan.
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