Phase I Therapeutic Resistance of Prostate Cancer Mediated by Cadherin T6

摘要

This phase I project characterized a gene product initially referred to as 'T6' that is upregulated when cultured prostate cancer cells were selected for an apoptosis-resistance phenotype. We have characterized this molecule and now call it protocadherin-PC. It is a very unusual species of protocadherin family molecules in that it is localized cytoplasmically instead of membrane-bound (like other members of this family) and we have shown that it binds to the wnt-signaling transcription factor, P-catenin, activating transcription from beta-catenin/TCF promotors. Thus, expression of protocadherin-PC in prostate cancer cells appears to activate the wnt signaling pathway in an analgous manner to which writ signaling is activated during progression of colon cancer or melanoma. We have also found that this unique protocadherin is encoded on the human Y chromosome and we have shown that the Y-chromosomal form of protocadherin-PC is highly upregulated in actual specimens of hormone-resistant prostate cancers in conjunction with activation of the writ- signaling pathway. Therefore, the results of this project suggest that activation of the wnt- signaling pathway by protocadherin-PC has an important role in the development of therapeutic resistance in prostate cancer patients.