Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of death among US males. A hallmark of human prostate cancer is resistance to apoptosis in response to treatment. Photodynamic Therapy (PDT), which uses a photosensitizer and red light, offers the advantage of potent induction of apoptosis and independence of growth rate, cell cycle, and androgen sensitivity. The proposed research is based on our recent observation that the tyrosine kinase Etk counters apoptosis in human prostate cancer cells. The primary hypotheses are: (a) mitochondria are the principal targets of PDT-induced apoptosis in prostate cancer cells; (b) the critical PDT lesions directly activate apoptosis; and (c) Etk has both chronic and acute effects on mitochondrial function that result in inhibition of apoptosis. To test the hypotheses, the photocytotoxic responses of related cell lines derived from androgen-sensitive LNCaP and androgen-independent DU145 cells will be studied: parental, Etk-overexpressing, Etk-dominant negative, and Bcl-2-overexpressing.
In Aim 1, we will elucidate the role of growth rate and cell cycle distribution in photocytotoxicity.
In Aim 2, we will determine whether or not Etk expression results in blockage of release of cytochrome c from mitochondria of PDT-treated cells and thereby downstream events in apoptosis.
In Aim 3, we will determine whether or not Etk influences the level of initial mitochondrial damage by PDT, including the formation of reactive oxygen species, loss of the mitochondrial membrane potential, and inhibition of respiration.
In Aim 4, we will study the role of Etk expression in regulating levels and phosphorylation status of members of the Bcl-2 family. The proposed research will elucidate cellular mechanisms of resistance to apoptosis in prostate cancer cells. Although the focus will be on PDT, the knowledge obtained should be applicable to many prostate cancer treatment modalities.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA083917-03
Application #
6514236
Study Section
Radiation Study Section (RAD)
Program Officer
Stone, Helen B
Project Start
2000-06-01
Project End
2003-09-29
Budget Start
2002-06-01
Budget End
2003-09-29
Support Year
3
Fiscal Year
2002
Total Cost
$309,825
Indirect Cost
Name
Case Western Reserve University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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