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West Virginia IDeA Network of Biomedical
Research Excellence |
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Albert Magro
Fairmont State UniversityIntegrin
Regulation of Cell Death in Cancer Cells
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Abstract: A goal of this
proposal is to elucidate how integrin mediated focal adhesions
render glioblastomas (CRL-2610) and breast adenocarcinomas (MCF-7)
resistant to the pharmacological induction of apoptosis. A strategy
is to put to advantage the differences between CRL-2610 and MCF-7
cells which include: expressed integrins, caspase-3, wild-type p53,
Fas ligand activation, and 12-lipoxygenase (12-Lox) expression. An
aim is to modulate the expression of integrins in both cell lines
and demonstrate that the susceptibility and resistance to the
pharmacological induction of apoptosis correlates with the degree of
integrin mediated focal adhesions. An additional aim is to
demonstrate that the expression of integrins and degree of focal
adhesions is mediated by c-Myb in the glioblastomas and by 12-Lox in
MCF-7 cells. Preliminary data show that apoptosis and cell rounding
in CRL-2610 cells is accompanied by a precipitous drop in c-myb
expression, while cell rounding and apoptosis is induced by the
inhibition of 12-Lox in MCF-7 cells. It is reported that c-Myb and
12-Lox mediate the expression of alpha and beta subunits of
integrins in epithelial and endothelial cells. When c-Myb and 12-Lox
are blocked in endothelial cells angiogenesis is inhibited. This is
of interest for a chemotherapeutic approach that could induce
apoptosis, while inhibiting angiogenesis, would simultaneously
involve two important strategies for the treatment of malignancies.
An intent is to elucidate anti-apoptotic cell signaling pathways
transduced by integrins through the phosphorylation of the focal
adhesion kinase (FAK). The interplay between the integrin-mediated-anti-apoptotic
FAK-Akt pathway and the pharmacologically induced mitochondrial
apoptotic pathway in the two cell types will be determined. The
overall objective of this proposal is to obtain knowledge of the
pro-apoptotic and anti-apoptotic machinery of focal adhesions in a
way that will be useful to the development of effective apoptotic
inducing chemotherapeutic agents in cancer cells.
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