Arthritis
Type 2 Diabetes
Circ Res.
2006 May 25; [Epub ahead of print] Int J Gastrointest Cancer.
2005;36(3):131-46.
Integrin-Mediated Transcriptional Activation of Inhibitor of Apoptosis
Proteins Protects Smooth Muscle Cells Against Apoptosis Induced by Degraded
Collagen.
von
Wnuck Lipinski K, Keul P, Ferri N, Lucke S, Heusch G, Fischer
JW, Levkau B.
Institute of Pathophysiology, Center of Internal
Medicine, University Hospital, Essen, Germany; Department of
Pharmacological Sciences, University of Milan, Italy; and Molecular
Pharmacology, Institute of Pharmacology and Clinical Pharmacology,
Heinrich-Heine University Dusseldorf,
Germany.
Apoptosis of smooth muscle cells (SMC) and degradation of the extracellular matrix (ECM) have both been implicated in
atherosclerotic plaque rupture. We have previously reported that degraded
type I collagen fragments induce a rapid but transient apoptotic burst
initiated by calpains in SMC. The aim of the
current study was to identify the pathway responsible for consecutive SMC
survival. We show that exposure of SMC to collagen fragments resulted in a
sustained activation of nuclear factor (NF)-kappaB
via phosphorylation and degradation of IkappaBalpha. Its prevention through retroviral
expression of superrepressor IkappaBalpha
or proteasome inhibition potently induced
apoptosis. In the presence of blocking antibodies to alphavbeta3 integrin and RGD peptides, collagen fragments no longer
activated NF-kappaB and apoptosis was enhanced.
The mechanism by which NF-kappaB was protecting
SMC against collagen fragment-induced apoptosis was a transcriptional
activation of several endogenous caspase
inhibitors of the inhibitor of apoptosis protein (IAP) family as: (1) the
expression of xIAP, c-IAP2, and survivin was potently induced by collagen fragments;
(2) IAP expression was abrogated by superrepressor
IkappaBalpha; and (3) knockdown of each of the 3 IAPs by small interfering RNA (siRNA)
resulted in enhanced apoptosis after collagen fragment treatment. Our data
suggest that SMC exposed to degraded collagen are protected against
apoptosis by a mechanism involving alphavbeta3-dependent NF-kappaB activation with consequent activation of IAPs. This may constitute a novel antiapoptotic
pathway ensuring SMC survival in settings of enhanced ECM degradation such
as cell migration, vascular remodeling, and atherosclerotic plaque rupture.
PMID: 16728660 [PubMed - as supplied by
publisher]
Type I Collagen and Divalent Cation Shifts Disrupt Cell-Cell Adhesion, Increase
Migration, and Decrease PTHrP, IL-6, and IL-8
Expression in Pancreatic Cancer Cells.
Grzesiak JJ, Smith
KC, Chalberg C, Burton
DW, Deftos LJ, Bouvet M.
Department of Surgery, University of California, San Diego and Veterans
Affairs, San Diego Healthcare System, San Diego, CA 92161.
Background:We have shown in FG pancreatic cancer
cells that alpha2beta1 integrin-mediated type I
collagen adhesion decreases parathyroid hormone-related protein (PTHrP), interleukin-6 (IL-6), and interleukin-8 (IL-8)
expression, decreases the localization of E-cadherin
and beta-catenin in cell-cell contacts, increases
cell migration, and increases glycogen synthase kinase 3 (GSK3) and protein kinase
B (PKB/Akt) phosphorylation
states relative to alpha5beta1 integrin-mediated fibronectin (Fn) adhesion. Aim of the Study: To extend
our observations in FG cells to other pancreatic cancer cell lines, and to
determine whether E-cadherin-mediated cell-cell
adhesion and its downstream effectors were functionally involved in the
ECM-mediated regulation of PTHrP, IL-6, and IL-8.
Methods: We used standard biochemical techniques to determine ECM-specific
differences in E-cadherin and beta-catenin localization, GSK3 and PKB/Akt
phosphorylation, haptokinetic
cell migration, and cytokine expression in pancreatic cancer cells. We also
conducted functional studies using pharmacological inhibitors for GSK3 and
PKB/Akt, as well as elevated Mg2+/Ca2+ ratios
similar to pancreatic juice, and examined their effects on cytokine
expression. Results: Differences in E-cadherin
and beta-catenin localization along with GSK3 and
PKB/Akt phosphorylation
occur in multiple pancreatic cancer cell lines, resulting in differences in
ECM-mediated haptokinesis and cytokine expression
that are generally consistent with previous observations in FG cells. Our
functional studies also suggest that E-cadherin-mediated
cell-cell adhesion and downstream effectors are involved in PTHrP, IL-6, and IL-8 expression. Conclusions: These
data indicate that alpha2beta1 integrin-mediated
type I collagen adhesion disrupts cell-cell adhesion architecture,
resulting in increased migration and decreased PTHrP,
IL-6, and IL-8 expression in pancreatic cancer cells.
PMID: 16720909 [PubMed - in process]