Induction of the p75NTR by Aryl Propionic Acids in Prostate Cancer Cells
Annual rept. 1 Dec 2006-30 Nov 2007
GEORGETOWN UNIV WASHINGTON DC
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The p75 neurotrophin receptor p75NTR is a tumor suppressor in the prostate whose expression decreases as prostate cancer progresses. The purpose of this project is to investigate the role of p75NTR in the observed anticancer activity of aryl propionic acids in the prostate. I have found that treatment of prostate cancer cells with the aryl propionic acids R-flurbiprofen and ibuprofen induces reexpression of p75NTR, decreases cell survival, and increases apoptosis. In addition, p75NTR was the only apoptosis inducing death receptor that was significantly upregulated by treatment. Transfection of two different dominant negative forms of p75NTR or p75NTR siRNA before treatment partially rescued the cells from decreased cell survival. Therefore, induction of p75NTR by R-flurbiprofen and ibuprofen is at least partially causal of the observed decreased survival. Investigation into the mechanism of p75NTR induction by R-flurbiprofen and ibuprofen revealed a strong correlation between increased p75NTR protein level and increased p75NTR mRNA level. In addition, the increase in mRNA appears to be the result of increased mRNA stability. Finally, induction of p75NTR seems to be dependent on the p38 MAPK pathway, which is involved in regulating mRNA stability of a subset of transcripts.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research