Cell death by apoptosis results in the removal of individual cells from the midst of a living tissue without damage to surrounding tissue. In recent years, it has been recognized that resistance to apoptosis is a hallmark of cancers and that resistance to chemotherapy can stem from a failure in apoptotic signal transmission. We have found that high levels of glucose metabolism, as is typically seen in cancer cells, can potently suppress apoptosis. In particular, we have found that the initiator caspase, caspase 2 (C2), activated in response to a number of chemotherapeutic agents, is suppressed when pentose phosphate pathway (PPP) activity is high. We have found that abundant NADPH, produced by the PPP, promotes activation of the kinase CaMKII to phosphorylate and suppress C2. Binding of phosphorylated C2 by the small acidic protein 14-3-3? prevents C2 dephosphorylation, dimerization, and activation. Conversely, when glucose or other nutrients are scarce, 14-3-3 ? is released from C2 to allow dephosphorylation and activation. We have recently found that 14- 3-3 ? binding to C2 is impeded by acetylation when nutrients are depleted (so that the PPP cannot operate) and that 14-3-3 ? deacetylation, catalyzed by the sirtuin, Sirt1, is stimulated under nutrient replete conditions.
The aims of this grant are 1) to delineate the molecular pathways linking NADPH and CaMKII, 2) to determine how Sirt1 is regulated to control 14-3-3 ?-C2 interactions and 3) to determine whether chemoresponsiveness of breast cancer cells can be altered by manipulating the pathways linking metabolism and C2.
The goal of this grant is to determine how metabolism regulates the apoptotic protease, caspase 2 and to determine how metabolic manipulation might be used to enhance caspase-2 activation. As caspase 2 has been implicated in the response to some chemotherapeutic agents, this work may provide avenues for enhancing the response to cancer chemotherapy.
|Yang, C-S; Matsuura, K; Huang, N-J et al. (2015) Fatty acid synthase inhibition engages a novel caspase-2 regulatory mechanism to induce ovarian cancer cell death. Oncogene 34:3264-72|
|Machado, M V; Michelotti, G A; Pereira, T de Almeida et al. (2015) Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis. Gut 64:1148-57|
|Yang, C-S; Sinenko, S A; Thomenius, M J et al. (2014) The deubiquitinating enzyme DUBAI stabilizes DIAP1 to suppress Drosophila apoptosis. Cell Death Differ 21:604-11|
|Huang, Bofu; Yang, Chih-Sheng; Wojton, Jeffrey et al. (2014) Metabolic control of Ca2+/calmodulin-dependent protein kinase II (CaMKII)-mediated caspase-2 suppression by the B55Î²/protein phosphatase 2A (PP2A). J Biol Chem 289:35882-90|
|Johnson, Erika Segear; Lindblom, Kelly R; Robeson, Alexander et al. (2013) Metabolomic profiling reveals a role for caspase-2 in lipoapoptosis. J Biol Chem 288:14463-75|
|Chen, Chen; Zhang, Liguo; Huang, Nai-Jia et al. (2013) Suppression of DNA-damage checkpoint signaling by Rsk-mediated phosphorylation of Mre11. Proc Natl Acad Sci U S A 110:20605-10|
|Andersen, Joshua L; Kornbluth, Sally (2013) The tangled circuitry of metabolism and apoptosis. Mol Cell 49:399-410|
|Kim, Jiyeon; Parrish, Amanda B; Kurokawa, Manabu et al. (2012) Rsk-mediated phosphorylation and 14-3-3É› binding of Apaf-1 suppresses cytochrome c-induced apoptosis. EMBO J 31:1279-92|
|Johnson, Erika Segear; Kornbluth, Sally (2012) Life, death, and the metabolically controlled protein acetylome. Curr Opin Cell Biol 24:876-80|
|Andersen, Joshua L; Thompson, J Will; Lindblom, Kelly R et al. (2011) A biotin switch-based proteomics approach identifies 14-3-3Î¶ as a target of Sirt1 in the metabolic regulation of caspase-2. Mol Cell 43:834-42|
Showing the most recent 10 out of 18 publications