The neurotrophin receptor, p75 NTR, binds the neurotrophin family (e.g. NGF) of growth factors. The p75 NTR is a member of the tumor necrosis factor receptor superfamily. Specific members of this superfamily, including the p75 NTR, share similar sequence motifs designated """"""""death domains"""""""" that signal initiation of apoptotic function and inhibition of growth. The p75 NTR exhibits an inverse association of protein expression with malignant progression of the human prostate. Furthermore, we have shown that the p75 NTR is a novel tumor suppressor in human prostate cancer. This is significant since the pathologic elimination of the p75 NTR tumor suppressor facilitates growth during malignant progression of the human prostate. To further elucidate the role of the p75 NTR as a tumor suppressor in the prostate we will test the hypothesis that a functional p75 NTR in prostate cancer cells modifies post-receptor effectors that regains inhibition of growth control. The mechanisms of action of p75 NTR mediated suppression of prostate growth will be assessed in the following five specific aims.
In aim 1, we will examine p75 NTR mediated death receptor signal transduction via both the NF-kappaB/I-kappaB pathway and/or activation of the JNK pathway as it relates to inhibition of proliferation and activation of apoptosis.
In aim 2, we will demonstrate p75 NTR dependent inhibition of prostate tumor cell growth via impeded progression of the cell cycle and changes in expression/activity of the cyclin/cdk holoenzyme complexes.
In aim 3, we will examine p75 wrR mediated induction of apoptosis as it relates to changes in the expression ofpro-apoptotic (e.g. Bax) and anti-apoptotic (e.g. Bcl-xL) effectors, and activation of the downstream caspase cascade.
In aim 4 we will examine the dual role of p75 NTR as a metastasis suppressor and establish a mechanistic relationship between p75 NTR dependent suppression of metastasis and induction of apoptosis and/or reduced cell proliferation in the metastatic prostate tumor cells.
In aim 5, we will demonstrate pre-clinical gene therapy application of p75 NTR vectors by intra-tumoral injection in SCID mice. These studies should elucidate the mechanism(s) of action of the p75 NTR as a tumor and metastasis suppressor of human prostate growth, and its potential application for gene therapy of prostate cancer.
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