2000 ASCB Annual Meeting Press Book - page 11

Taking Aim: A New Target
for Cancer Therapy
A cell from a breast tumor can travel to the bone,
where it can invade the bone tissue and form a new
tumor. This process is called metastasis, and it represents
the main health threat to women with breast cancer.
Japanese researchers Kazuyuki Itoh and Kiyoko Yoshioka
have identified a signaling pathway that controls how
breast cancer cells invade other tissues. They identified an
enzyme named LIM-kinase as a key player in this pathway.
The adhesion of tumor cells to target tissues, and their
subsequent migration are pivotal steps in invasion. The
Rho family of regulatory proteins control many aspects of
cell adhesion and movement, by regulating cell surface
adhesiveness and the cytoskeleton, which drives cell
movement. Rho proteins have several targets, including
the ROCK family of kinases. Kinases are enzymes that
physically modify other proteins by phosphorylation,
changing the properties or activities of these target pro-
teins. Thus, Rho proteins set off a chain reaction by affect-
ing ROCK kinases, which in turn regulate additional
‘downstream’ proteins.
Itoh and Yoshioka explored whether Rho and ROCK
kinases affect the invasive properties of cells. They found
that cultured cells that expressed higher levels of ROCK
activity were more active for invasion. The more ROCK,
the more aggressive the tumor became. Conversely, cells
that were forced to express a defective ROCK kinase had
significantly lower invasive properties. A specific inhibitor
of ROCK, named Y-27632, blocked both the Rho-mediated
effects on the cytoskeleton and the invasive activity. They
showed that continuous delivery of this inhibitor markedly
reduced the spread of hepatoma cells that were implanted
into the abdomen of rats.
Further experiments showed that one of the ROCK
kinase’s targets is yet another kinase: the LIM-kinase. LIM-
kinase regulates the dynamics of the actin cytoskeleton.
When introduced into human breast cancer cells, LIM-
kinase increased both the adhesion and invasiveness of
these cells, suggesting that LIM might normally promote
invasiveness. Treating these same breast cancer cells with
the ROCK inhibitor lowered their invasiveness. Itoh and
Yoshioka suggest that tissue invasion by tumor cells
involves signalling and countersignalling between the Rho
pathway, the ROCK kinase, and the LIM-kinase. Their dis-
covery raises the possiblity that inhibitors of LIM-kinase
could be valuable as molecular agents for cancer treat-
ment.
6
40th Annual Meeting
December 9-13, 2000
Moscone Convention Center, San Francisco
Contact:
Kazuyuki Itoh
Chief, Department of Biology
Osaka Medical Center for Cancer and
Cardiovascular Diseases
Tel: +81-6-6972-1181 x2325
Key molecules that regulate breast cancer cells
to invade new tissues
Authors:
Kazuyuki Itoh and Kiyoko Yoshioka,
Department of Biology, Osaka Medical Center
for Cancer and Cardiovascular Diseases, 1-3-3
Nakamichi, Higarashinari-ku, Osaka 537-8511,
Japan
At The ASCB Meeting
Poster Session Halls A/B/C
P23 - Cell Motility & Cytoskeleton I:
Pathogenesis
Author Presents
Sunday, December 10, 12:00 PM-1:30 PM
Program # 427
Board # B161
Human breast cancer cells (MCF-7) over-expressing LIM kinase
(lower panels) presented marked focal contacts stained with anti-
vinculin antibody (green) and enhanced thick stress fiber stained
with F-actin (red) in the cell body, compare to the control vector
transfected cells (upper panels, mock). The LIM kinase over-
expressing cells showed enhanced invasiveness.
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