Rac Affects Invasion of Human Renal Cell Carcinomas by
Up-regulating Tissue Inhibitor of Metalloproteinases (TIMP)-1 and
TIMP-2 Expression*
Rainer
Engers
§,
Erik
Springer,
Frits
Michiels¶,
John
G.
Collard¶, and
Helmut E.
Gabbert
From the Institute of Pathology,
Heinrich-Heine-University, Moorenstrasse 5, 40225 Duesseldorf, Germany
and the ¶ Division of Cell Biology, Netherlands Cancer Institute,
Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
Rho-like GTPases, including Cdc42, Rac1, and
RhoA, regulate distinct actin cytoskeleton changes required for
adhesion, migration, and invasion of cells. Tiam1 specifically
activates Rac, and earlier studies have demonstrated that Tiam1-Rac
signaling affects migration and invasion in a cell type- and cell
substrate-specific manner. In the present study, we examined the role
of Tiam1-Rac signaling in migration and invasion of human renal cell
carcinomas. Stable overexpression of Tiam1 or constitutively active
V12-Rac1 in a human renal cell carcinoma cell line (clearCa-28)
strongly inhibited cell migration by promoting E-cadherin-mediated
cell-cell adhesion. Blocking E-cadherin-mediated adhesion by
E-cadherin-specific HAV peptides allowed cells to migrate, but was not
sufficient to antagonize Tiam1- and V12-Rac1-induced inhibition of
Matrigel invasion, suggesting that Rac may influence invasion also
through other mechanisms. Indeed, Tiam1-mediated Rac activation induced
transcriptional up-regulation of tissue inhibitor of
metalloproteinases-1 (TIMP-1) and post-transcriptional up-regulation of
TIMP-2, whereas secretion and activity levels of their counterparts,
matrix metalloproteinase-9 and matrix metalloproteinase-2,
respectively, were not affected. Application of recombinant TIMP-1 and
TIMP-2 proteins significantly inhibited invasion of mock-transfected
clearCa-28 cells, supporting a role of TIMPs in Rac-mediated inhibition
of invasion. To our knowledge, this is the first evidence that
increased Rac signaling may inhibit invasion of epithelial tumor cells
by up-regulation of TIMP-1 and TIMP-2.
*
This work was supported by Deutsche Forschungsgemeinschaft
Grants Ga 326/4-1 and GA 326/4-3 and Dr. Mildred Scheel Stiftung für Krebsforschung Grant 10-1582-En I (to R. E. and H. E. G.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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