"BCL-XL Function "
Bcl-2 protein family members are central regulators of apoptosis with mitochondrial
sites of action. Treatment-refractory cancers from a variety of sites
display high expression of the pro-survival Bcl-XL factor. The Bcl-XL
inhibitor 2-methoxy antimycin (2-MeAA) is a promising anticancer agent that
kills multidrug-resistant tumor cells with high Bcl-XL expression.
The selectivity of targeted therapies for tumor cells versus normal cells
is often described as a consequence of tumor cell addiction to the targeted
activity (e.g. EGFR antagonists). Bcl-XL expression modifies carbon metabolic
flux in several cellular contexts. In the case of Bcl-XL, I propose
that the molecular basis of “target addiction” is the superposition of a
Bcl-XL metabolic function on the different metabolic states characteristic
of tumor and normal cells. The primary aim of this project is to test the
hypothesis that metabolic profiles of cancer cells and normal cells are modified
by Bcl-XL expression in different ways, and that this interaction determines
the consequences of acute Bcl-XL inhibition on cell viability. Two cell lines
will be compared, one with a metabolic shift to aerobic glycolysis characteristic
of tumor cells and one deriving ATP primarily from mitochondrial oxidative
phosphorylation, for Bcl-XL-mediated changes in carbon metabolism partitioning
with several carbon and nitrogen sources. These studies will take advantage
of a recently designed perfused biosensor system with capability for real-time
monitoring of cytochrome c redox state (mitochondrial electron transport),
and O2 consumption, offline measurements of media glucose/lactate and calculated
ATP/ADP/Pi phosphorylation potential. The relationship of metabolic
state to the “Bcl-XL- addicted” phenotype will be tested by measuring cytotoxic
and metabolic responses to the Bcl-XL inhibitor 2-MeAA.
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