Our overall goal is to determine mechanisms whereby genistein, the major isoflavone in soybeans, prevents growth and induces apoptosis of prostate cancer cells. Both prospective and retrospective epidemiologic studies indicate that soy products decrease the risk of prostate cancer. Laboratory studies support the epidemiology. This proposal asks specifically about the role of genistein and other nutrients as a response to metabolic stress, and whether genistein influences the stress response to specifically target cancer cells for death. In vivo, cancer cells are likely to be chronically metabolically stressed, because their unregulated growth taxes the capacity of existing or newly recruited vaculature. The metabolic stress proteins known as the glucose regulated proteins (GRPs) protect tumor cells from apoptosis, whereas the metabolic stress proteins known as growth-arrest-DNA-damage proteins (GADDs) cause growth arrest and apoptosis. The hypothesis to be tested is that genistein, by selectively inhibiting GRPs, but not GADDs, induces growth arrest and apoptosis of prostate cancer cells. This study will: 1) characterize the effects of genistein on mRNA and protein levels for the stress-related GRP genes (grp78 and grp94) and the GADD genes (GADD153 and GADD45) in cells before and after exposure to stress inducing agents, 2) compare the effects of genistein on growth and apoptosis of stressed and non-stressed cells, 3) compare the effects of genistein on growth arrest and apoptosis in cells that over-express grp78, a protective chaperonin, after treatment with stress-inducing agents, and 4) determine whether genistein acts synergistically with other dietary compounds, e.g. diindolylmethane-derived from cruciferous vegetables which induces expression of GADDs and determine whether the mechanism involves pathways of the ER-stress response. If our hypothesis is correct, the exciting implication is that this is a mechanism whereby certain bioactive compounds in food can specifically target cancer cells for death. Moreover, combinations of nutrients may work together and at lower concentrations to target cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100967-04
Application #
7069067
Study Section
Special Emphasis Panel (ZCA1-SRRB-U (J1))
Program Officer
Kim, Young Shin
Project Start
2003-06-19
Project End
2008-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
4
Fiscal Year
2006
Total Cost
$280,923
Indirect Cost
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Smith, Sunyata; Sepkovic, Daniel; Bradlow, H Leon et al. (2008) 3,3'-Diindolylmethane and genistein decrease the adverse effects of estrogen in LNCaP and PC-3 prostate cancer cells. J Nutr 138:2379-85
Savino 3rd, John A; Evans, Jodi F; Rabinowitz, Dorianne et al. (2006) Multiple, disparate roles for calcium signaling in apoptosis of human prostate and cervical cancer cells exposed to diindolylmethane. Mol Cancer Ther 5:556-63
Sun, Shishinn; Han, Jing; Ralph Jr, Walter M et al. (2004) Endoplasmic reticulum stress as a correlate of cytotoxicity in human tumor cells exposed to diindolylmethane in vitro. Cell Stress Chaperones 9:76-87