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.
| 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 |
