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N-Cadherin in Prostate Cancer: Downstream Pathways and Their Translational Application for Castrate-Resistant Prostate Cancer

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Final rept. 27 Aug 2009-26 Aug 2012

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Current literature suggests that the activation of the androgen receptor AR pathway in metastatic castrate resistant prostate cancer CRPC, to be a driving force for resistance, yet AR is not ubiquitously expressed in cancer cells, suggesting there are alternate mechanisms for independence of AR. Overexpression of N-cadherin caused invasion, metastasis and castrate resistance in multiple models of CRPC and in clinical samples. It has been shown that N-cadherin is a possible marker of epithelial mesenchymal transition EMT. We looked at the N-cadherin driven signaling events in CRPC cells that can induce aggressive biologic effects, as well as the requirement of N-cadherin domains for these effects. We reported that N-cadherin overexpression activated NF-kappa B pathway, of which blockade inhibited invasion. N-cadherin overexpression also caused increased PI3KAKT activity which further mediated NF-kB activation. The combination of N-cadherin antibody and PI3K inhibitor showed in vitro synergistic effect in blocking invasion but not growth. The extracellular N-cadherin domain is critical for cell migration and invasion while the cytoplasmic domain is dispensable. Full length intact N-cadherin is required for in vitro castrate resistant growth of prostate cancer cells. In vivo studies were conducted to confirm these findings. We have tried to build our understanding of the signaling events that occur as a result of N-cadherin expression to identify biochemical targets that can be used therapeutically in combination with our N-cadherin antibody to achieve additive or synergistic anti-tumor activity.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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