Caspases, a family of cysteine proteases, are central to most cell death programs and therefore present an attractive target for therapeutic interventions. The investigators have shown that the PKC signal transduction pathway regulates anticancer drug sensitivity although the mechanism of regulation is incompletely understood. There are three classes of PKC isozymes-conventional (alpha, beta1, beta2 and gamma), novel (delta, epsilon, eta, theta and mu) and atypical (zeta and lambda / iota). Novel PKC isozymes are substrates for caspases and proteolytic activation of these isozymes has been linked to cell death. The preliminary study showed that PKC can also influence activation of caspases by apoptotic stimuli, suggesting that the PKC signal transduction pathway can be targeted to increase cell death by apoptotic stimuli. The investigators hypothesize that PKC functions not only downstream of caspases but also upstream of caspases to regulate caspase activation and cell death by chemotherapeutic drugs and that both the catalytic fragment and holoenzyme of PKC decide cell survival and cell death.
The Specific Aims are: (1) to delineate which steps of the cisplatin-induced caspase cascade are regulated by PKC; (2) to determine the functional significance of PKC activation and down-regulation on cisplatin-induced cell death and; (3) to establish whether deregulation in the PKC signal transduction pathway affects caspase activation and cisplatin resistance.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA085682-04
Application #
6690780
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Lees, Robert G
Project Start
2001-01-01
Project End
2006-12-31
Budget Start
2004-01-01
Budget End
2006-12-31
Support Year
4
Fiscal Year
2004
Total Cost
$205,367
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
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
Dhar, Rohini; Basu, Alakananda (2008) Constitutive activation of p70 S6 kinase is associated with intrinsic resistance to cisplatin. Int J Oncol 32:1133-7
Basu, Alakananda; Adkins, Brett; Basu, Chandreyi (2008) Down-regulation of caspase-2 by rottlerin via protein kinase C-delta-independent pathway. Cancer Res 68:2795-802
Mohanty, Sanghamitra; Huang, Jie; Basu, Alakananda (2005) Enhancement of cisplatin sensitivity of cisplatin-resistant human cervical carcinoma cells by bryostatin 1. Clin Cancer Res 11:6730-7
Persaud, Shalini D; Hoang, Van; Huang, Jie et al. (2005) Involvement of proteolytic activation of PKCdelta in cisplatin-induced apoptosis in human small cell lung cancer H69 cells. Int J Oncol 27:149-54
Kumar Biswas, Swarajit; Huang, Jie; Persaud, Shalini et al. (2004) Down-regulation of Bcl-2 is associated with cisplatin resistance in human small cell lung cancer H69 cells. Mol Cancer Ther 3:327-34
Lu, Dongmei; Huang, Jie; Basu, Alakananda (2004) Deregulation of PKB influences antiapoptotic signaling by PKC in breast cancer cells. Int J Oncol 25:671-6
Huang, Jie; Mohanty, Sanghamitra; Basu, Alakananda (2004) Cisplatin resistance is associated with deregulation in protein kinase C-delta. Biochem Biophys Res Commun 316:1002-8
Basu, Alakananda (2003) Involvement of protein kinase C-delta in DNA damage-induced apoptosis. J Cell Mol Med 7:341-50
Basu, Alakananda; Miura, Ayako (2002) Differential regulation of extrinsic and intrinsic cell death pathways by protein kinase C. Int J Mol Med 10:541-5

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