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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM080333-06
Application #
8466986
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Maas, Stefan
Project Start
2007-09-21
Project End
2016-02-29
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
6
Fiscal Year
2013
Total Cost
$309,659
Indirect Cost
$112,424
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Sinenko, Sergey A (2017) Proapoptotic function of deubiquitinase DUSP31 in Drosophila. Oncotarget 8:70452-70462
Matsuura, K; Huang, N-J; Cocce, K et al. (2017) Downregulation of the proapoptotic protein MOAP-1 by the UBR5 ubiquitin ligase and its role in ovarian cancer resistance to cisplatin. Oncogene 36:1698-1706
Foss, Kristen M; Robeson, Alexander C; Kornbluth, Sally et al. (2016) Mitotic phosphatase activity is required for MCC maintenance during the spindle checkpoint. Cell Cycle 15:225-33
Batchvarov, Iordan Stefanov; Taylor, Rachel Williamson; Bustamante-MarĂ­n, Ximena et al. (2016) A grafted ovarian fragment rescues host fertility after chemotherapy. Mol Hum Reprod 22:842-851
Kornbluth, Sally; Fissore, Rafael (2015) Vertebrate Reproduction. Cold Spring Harb Perspect Biol 7:a006064
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 B55?/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

Showing the most recent 10 out of 23 publications