We have demonstrated a suppression of ras oncogene induced transformation of NIH3T3 cells by several protease inhibitors, including antipain. We propose to investigate cellular and molecular mechanisms responsible for this activity of protease inhibitors. These studies will include reconstitution and other experiments to evaluate the role of growth conditions and cellular interactions in transformation suppression. We will test the hypothesis that the action of protease inhibitors is related to effects on endogenous oncogene expression, and determine whether the expression or incorporation of the transfected gene is affected by these agents. New techniques such as polymerase chain reaction will be employed to examine these parameters in the fraction of cells that have undergone stable transfection. Both sustained and transient alterations in gene expression will be measured. We will expand our initial studies to examine the effects of protease inhibitors on cell transformation induced by enhanced expression of proto-ras, as well as the NIH3T3 transforming genes neu, raf, met, and hst. We will also use alternative cell systems such as C3H/10T 1/2 and primary rat embryo fibroblasts to determine whether protease inhibitor suppression of transformation by oncogenes can be observed in cell types less sensitive to ras than NIH3T3. These experiments will provide important mechanistic information, and will define the generality of our initial findings. Finally, we will test other protease inhibitors such as Bowman-Birk inhibitor and potato inhibitor to develop an activity spectrum of protease inhibitors in this assay. It is anticipated that the experiments described in this application will provide important information regarding the mechanisms of action of an important class of anti-carcinogens - the protease inhibitors - at a molecular level using a defined target gene. Increased knowledge of oncogene transformation pathways, and development of a useful assay for the anti-neoplastic activity of protease inhibitors and other agents, are also likely to come from this research.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA052925-01
Application #
3197760
Study Section
Special Emphasis Panel (SRC (52))
Project Start
1990-08-01
Project End
1993-07-31
Budget Start
1990-08-01
Budget End
1991-07-31
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
New York University
Department
Type
Schools of Medicine
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012
Chen, Liqun; Bourguignon, Lilly Y W (2014) Hyaluronan-CD44 interaction promotes c-Jun signaling and miRNA21 expression leading to Bcl-2 expression and chemoresistance in breast cancer cells. Mol Cancer 13:52
Hubbard, F C; Cosma, G; Garte, S J (1996) Effects of mutationally activated Ha-ras on c-fos expression kinetics in rat tracheal epithelial cells. Mol Carcinog 16:77-82
Cosma, G; Hubbard, F; Jamasbi, R J et al. (1994) Role of H-ras in the malignant progression of rat tracheal epithelial cells. J Cancer Res Clin Oncol 120:641-4
Cox, L R; Motz, J; Troll, W et al. (1991) Antipain-induced suppression of oncogene expression in H-ras-transformed NIH3T3 cells. Cancer Res 51:4810-4
Cox, L R; Motz, J; Troll, W et al. (1991) Effects of retinoic acid on NIH3T3 cell transformation by the H-ras oncogene. J Cancer Res Clin Oncol 117:102-8