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2013 ; 3
(3
): 386-407
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Regulation of cytoskeleton organization by sphingosine in a mouse cell model of
progressive ovarian cancer
#MMPMID24970173
Creekmore AL
; Heffron CL
; Brayfield BP
; Roberts PC
; Schmelz EM
Biomolecules
2013[Jul]; 3
(3
): 386-407
PMID24970173
show ga
Ovarian cancer is a multigenic disease and molecular events driving ovarian
cancer progression are not well established. We have previously reported the
dysregulation of the cytoskeleton during ovarian cancer progression in a
syngeneic mouse cell model for progressive ovarian cancer. In the present
studies, we investigated if the cytoskeleton organization is a potential target
for chemopreventive treatment with the bioactive sphingolipid metabolite
sphingosine. Long-term treatment with non-toxic concentrations of sphingosine but
not other sphingolipid metabolites led to a partial reversal of a cytoskeleton
architecture commonly associated with aggressive cancer phenotypes towards an
organization reminiscent of non-malignant cell phenotypes. This was evident by
increased F-actin polymerization and organization, a reduced focal adhesion
kinase expression, increased a-actinin and vinculin levels which together led to
the assembly of more mature focal adhesions. Downstream focal adhesion signaling,
the suppression of myosin light chain kinase expression and hypophosphorylation
of its targets were observed after treatment with sphingosine. These results
suggest that sphingosine modulate the assembly of actin stress fibers via
regulation of focal adhesions and myosin light chain kinase. The impact of these
events on suppression of ovarian cancer by exogenous sphingosine and their
potential as molecular markers for treatment efficacy warrants further
investigation.