Interdisciplinary Training

Pam Schwartz

"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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