1: Br J Cancer. 2002 Jul 29;87(3):348-51.
Integrin alpha(v)beta6-associated ERK2 mediates MMP-9 secretion in colon cancer
cells.
Gu X, Niu J, Dorahy DJ, Scott R, Agrez MV.
Newcastle Bowel Cancer Research Collaborative, Hunter Medical Research
Institute, John Hunter Hospital and The University of Newcastle, NSW 2308,
Australia.
There is general consensus that matrix metalloproteinases are involved in tumour
progression. We show herein that inhibition of integrin alpha(v)beta6 expression
in colon cancer cells suppresses MMP-9 secretion. This integrin-mediated event
is dependent upon direct binding between the beta6 integrin subunit and
extracellular signal-regulated kinase 2. Targetting either beta6 or its
interaction with extracellular signal-regulated kinase in order to inhibit
matrix metalloproteinase activity may offer a useful therapeutic approach in
preventing growth and spread of colon cancer. Copyright 2002 Cancer Research UK
PMID: 12177807 [PubMed - indexed for MEDLINE]
2: Int J Cancer. 2002 Jun 1;99(4):529-37.
Integrin expression in colon cancer cells is regulated by the cytoplasmic domain
of the beta6 integrin subunit.
Niu J, Dorahy DJ, Gu X, Scott RJ, Draganic B, Ahmed N, Agrez MV.
Newcastle Bowel Cancer Research Collaborative, Hunter Medical Research
Institute, John Hunter Hospital, The University of Newcastle, Callaghan, New
South Wales 2310, Australia.
We have previously reported that the alphavbeta6 integrin upregulates its own
expression in a protein kinase C-dependent manner with increasing cell density.
The wild-type beta6 integrin subunit has also been shown to promote tumour
growth in vivo and its growth-enhancing effect is regulated by both a MAP kinase
binding motif on beta6 and the 11 amino acid C-terminal cytoplasmic extension
unique to the beta6 subunit. Herein, we show that the 11 amino acid cytoplasmic
extension is essential for the cell density-dependent increase in beta6
expression and that the 11 amino acid tail exerts a dominant negative effect on
cell density- and PKC-mediated beta5 expression in alphavbeta6-expressing colon
cancer cells. Cells that express beta6 lacking the 11 amino acid tail respond to
PKC simulation with increased expression of only the beta5 subunit as seen for
cells that lack constitutive alphavbeta6 expression. In contrast, loss of the
ERK binding site on beta6 markedly impairs cell density- and PKC-dependent
expression of either beta6 or beta5 in the presence or absence of the 11 amino
acid tail, respectively. Our findings suggest that in alphavbeta6-expressing
cells, a hierarchy of kinase signalling cascades exists and that the beta6-ERK2
interaction dominates over PKC-mediated signalling pathways responsible for
integrin upregulation with cell confluence. Given the dominance of the
beta6-ERK2 interaction over PKC-mediated expression of both beta5 and beta6
integrin subunits, targeting the beta6-ERK2 interaction may prove useful as an
anticancer strategy in colon cancer. Copyright 2002 Wiley-Liss, Inc.
PMID: 11992542 [PubMed - indexed for MEDLINE]
3: Oncogene. 2002 Feb 21;21(9):1370-80.
Direct integrin alphavbeta6-ERK binding: implications for tumour growth.
Ahmed N, Niu J, Dorahy DJ, Gu X, Andrews S, Meldrum CJ, Scott RJ, Baker MS,
Macreadie IG, Agrez MV.
Gynaecological Cancer Research Centre, The Royal Women's Hospital, Melbourne and
University of Melbourne, Melbourne, Australia.
Blockade of the mitogen-activated protein (MAP) kinase pathway suppresses growth
of colon cancer in vivo. Here we demonstrate a direct link between the
extracellular signal-regulated kinase ERK2 and the growth-promoting cell
adhesion molecule, integrin alphavbeta6, in colon cancer cells. Down-regulation
of beta6 integrin subunit expression inhibits tumour growth in vivo and MAP
kinase activity in response to serum stimulation. In alphavbeta6-expressing
cells ERK2 is bound only to the beta6 subunit. The increase in cytosolic MAP
kinase activity upon epidermal growth factor stimulation is all accounted for by
beta6-bound ERK. Deletion of the ERK2 binding site on the beta6 cytoplasmic
domain inhibits tumour growth and leads to an association between ERK and the
beta5 subunit. The physical interaction between integrin alphavbeta6 and ERK2
defines a novel paradigm of integrin-mediated signalling and provides a
therapeutic target for cancer treatment.
PMID: 11857080 [PubMed - indexed for MEDLINE]
4: Int J Cancer. 2001 Apr 1;92(1):40-8.
The alphaVbeta6 integrin regulates its own expression with cell crowding:
implications for tumour progression.
Niu J, Gu X, Ahmed N, Andrews S, Turton J, Bates R, Agrez M.
Discipline of Surgical Science, Faculty of Medicine and Health Sciences,
University of Newcastle, New South Wales, Australia.
Expression of the growth-promoting integrin alphavbeta6 in colon cancer cells
induces gelatinase B secretion and activation, the inhibition of which abolishes
alphavbeta6-mediated tumour cell growth within a collagen matrix. Herein, we
show that high cell density selectively enhances alphavbeta6 expression in a
protein kinase C (PKC)-dependent manner in preference to other beta integrin
subunits, resulting in a marked increase in gelatinase B secretion as cells
reach confluence. Moreover, PKC activity increases with cell confluence, and the
rise in PKC activity is much greater for alphavbeta6-expressing cells than for
colon cancer cells which lack alphavbeta6. We propose a self-perpetuating system
of colon cancer progression in which the integrin alphavbeta6 provides a means
of sustaining tumour cell proliferation. In this model, alphavbeta6 regulates
its own expression via a PKC-mediated signalling pathway as tumour cells become
crowded and quiescent. The alphavbeta6-mediated induction of gelatinase B
secretion facilitates peri-cellular matrix degradation, which helps overcome
crowding and restores cell proliferation. Copyright 2001 Wiley-Liss, Inc.
PMID: 11279604 [PubMed - indexed for MEDLINE]
5: Int J Cancer. 1999 Mar 31;81(1):90-7.
The alpha v beta 6 integrin induces gelatinase B secretion in colon cancer
cells.
Agrez M, Gu X, Turton J, Meldrum C, Niu J, Antalis T, Howard EW.
Discipline of Surgical Science, Faculty of Medicine and Health Sciences,
University of Newcastle, Callaghan, Australia.
magrez@mail.newcastle.edu.auIn human cancers, the co-operative role between cell-adhesion receptors and
proteases capable of degrading matrix barriers remains poorly understood. We
have previously reported that the epithelium-restricted integrin alpha(v)beta6
becomes highly expressed in colon cancer compared with normal mucosa and that
heterologous expression of alpha(v)beta6 in colon cancer cells is associated
with enhanced cell growth. Herein, we report that alpha(v)beta6 expression in
colon cancer cells leads to a relative increase in secretion of the matrix
metalloproteinase gelatinase B over its respective inhibitor and that this
secretion parallels the level of cell-surface beta6 expression. The
alpha(v)beta6-mediated gelatinase B secretion is associated with increased
proteolysis of denatured collagen at the cell surface, and inactivation of
gelatinase B in beta6-expressing tumour cells inhibits cell spreading and
proliferation within 3-dimensional collagen matrices. Our findings suggest that
alpha(v)beta6-mediated gelatinase B secretion is important in the progression of
human colon cancer.
PMID: 10077158 [PubMed - indexed for MEDLINE]
6: Biochem Biophys Res Commun. 1998 Aug 10;249(1):287-91.
Integrin-mediated signalling of gelatinase B secretion in colon cancer cells.
Niu J, Gu X, Turton J, Meldrum C, Howard EW, Agrez M.
Discipline of Surgical Science, Faculty of Medicine and Health Sciences,
University of Newcastle, New South Wales, Australia.
The progression of colon cancer has been linked to both cell adhesion molecules
called integrins and matrix-degrading enzymes called metalloproteinases. Herein
we report that the alpha v beta 6 integrin expressed in colon cancer cells
induces gelatinase B secretion through the C-terminal cytoplasmic extension
unique to the beta 6 integrin subunit, and that this ligand-independent event
involves activation of the protein-kinase-C pathway.
PMID: 9705874 [PubMed - indexed for MEDLINE]
