Metabolic Regulation of Caspase 2 in Breast Cancer
Annual summary 1 Apr 2008-31 Mar 2011
DUKE UNIV DURHAM NC
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A major obstacle impeding the use of cytotoxic agents in breast cancer treatment is the cancer cell s ability to evade cell death pathways. Therapies which induce apoptosis in otherwise resistant cancer cells have the potential to treat a variety of cancers, including breast cancer. Our research focuses on the apical apoptotic enzyme caspase 2 C2, which has been proposed as a critical activating protease for breast cancer chemotherapeutic agents such as doxorubicin and etoposide, as well as other genotoxic agents. Our lab has previously shown that C2 is held inactive by nutrient flux through the pentose phosphate pathway PPP. C2 inactivation in response to nutrient abundance is a consequence of C2 phosphorylation by CaMKII, which prevents downstream engagement of the executioner pathway. CaMKII is itself activated by the PPP byproduct NADPH. We will determine the mechanism of CaMKII activation and subsequent C2 inhibition by NADPH is still unknown. Additionally, we will determine whether via metabolic profiling whether breast cancer metabolism confers resistance to apoptosis.
- Medicine and Medical Research