Apoptosis is a highly orchestrated cell suicidal program required to maintain a balance between cell proliferation and cell death. Tumor necrosis factor-a (TNF), a pleotropic cytokine, plays an important role in immunesurveillance. The interaction of TNF with its receptors triggers activation of a family of cysteine proteases or caspases that are essential for the execution of cell death by apoptosis. The ability to evade cell death pathway is a critical event in cancer progression. Various pro- and antiapoptotic signal transduction pathways regulate activation of caspases by TNF. Protein kinase C (PKC), a family of serine/threonine kinases, plays a critical role in growth factor signal transduction pathway. During our previous funding period, we have shown that novel PKC isozymes act as anti-apoptotic proteins to inhibit cell death by TNF. The abundance of novel PKCs, however, was not sufficient to explain cellular sensitivity/resistance to TNF. A deregulation in Akt/protein kinase B (PKB) signal transduction pathway has been associated with the genesis of several cancers, including breast cancer although the molecular mechanism(s) by which this signaling pathway contributes to breast cancer pathogenesis is incompletely understood. We hypothesize that the PKC signal transduction pathway cooperates with components of the phosphatidylinositol 3-kinase (PI3K) pathway, such as PKB to regulate cell survival and cell death. The overall objective of this grant proposal is to delineate how a deregulation in PI3K/PKB signaling pathway that exists in breast cancer cells influences anti-apoptotic signaling by PKC. The long-term objective is to develop strategies to intervene with these pathways to inhibit progression of breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA071727-04A2
Application #
6782397
Study Section
Special Emphasis Panel (ZRG1-CBSS (02))
Program Officer
Spalholz, Barbara A
Project Start
1997-09-04
Project End
2009-02-28
Budget Start
2004-03-15
Budget End
2005-02-28
Support Year
4
Fiscal Year
2004
Total Cost
$255,600
Indirect Cost
Name
University of North Texas
Department
Microbiology/Immun/Virology
Type
Other Domestic Higher Education
DUNS #
110091808
City
Fort Worth
State
TX
Country
United States
Zip Code
76107
Pal, Deepanwita; Outram, Shalini Persaud; Basu, Alakananda (2013) Upregulation of PKC? by PKC? and PDK1 involves two distinct mechanisms and promotes breast cancer cell survival. Biochim Biophys Acta 1830:4040-5
Pal, Deepanwita; Outram, Shalini Persaud; Basu, Alakananda (2012) Novel regulation of protein kinase C-ýý. Biochem Biophys Res Commun 425:836-41
Sridharan, Savitha; Basu, Alakananda (2011) S6 kinase 2 promotes breast cancer cell survival via Akt. Cancer Res 71:2590-9
Shankar, Eswar; Krishnamurthy, Soumya; Paranandi, Rajiv et al. (2010) PKCepsilon induces Bcl-2 by activating CREB. Int J Oncol 36:883-8
Basu, Alakananda; Pal, Deepanwita (2010) Two faces of protein kinase C?: the contrasting roles of PKC? in cell survival and cell death. ScientificWorldJournal 10:2272-84
Basu, Alakananda; Sridharan, Savitha; Persaud, Shalini (2009) Regulation of protein kinase C delta downregulation by protein kinase C epsilon and mammalian target of rapamycin complex 2. Cell Signal 21:1680-5
Dhar, Rohini; Persaud, Shalini D; Mireles, Joe R et al. (2009) Proteolytic cleavage of p70 ribosomal S6 kinase by caspase-3 during DNA damage-induced apoptosis. Biochemistry 48:1474-80
Basu, Alakananda (2008) Molecular targets of breast cancer: AKTing in concert. Breast Cancer 2:11-16
Basu, Alakananda; Persaud, Shalini D; Sivaprasad, Usha (2008) Manipulation of PKC isozymes by RNA interference and inducible expression of PKC constructs. Methods Enzymol 446:141-57
Shankar, E; Sivaprasad, U; Basu, A (2008) Protein kinase C epsilon confers resistance of MCF-7 cells to TRAIL by Akt-dependent activation of Hdm2 and downregulation of p53. Oncogene 27:3957-66

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