N-Cadherin in Prostate Cancer: Downstream Pathways and their Translational Application for Castrate-Resistant Prostate Cancer
Final rept. 27 Aug 2009-26 Aug 2012
CALIFORNIA UNIV LOS ANGELES
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Castration resistant prostate cancer CRPC is responsible for the overwhelming majority of prostate-cancer specific deaths. Although continued activation of the androgen receptor AR plays an important role in the development of castration resistance, AR-independent mechanisms represent an alternative source of biochemical signals that drive castration resistance. We have identified heightened expression of N-cadherin as a driving force in invasion, metastasis and castration resistance. Here we sought to identify biochemical signals that are regulated by N-cadherin in CRPC cells that can mediate the biologic effects of N-cadherin. In addition to activation of NF-kappa B reported in our first annual report, we have now identified the c-Jun N-terminal kinase JNK MAP kinase pathway as a signaling pathway that is activated in response to N-cadherin expression. We have generated inducible N-cadherin shRNA models to study the biochemical and cell biologic effects of N-cadherin. We have shown that N-cadherin activates JNK, which in turn phosphorylates the activator protein 1 AP1 transcription factor c-Jun. Phosphorylated c-Jun then heterodimerizes with c-Fos and drives expression of proteins including Twist, that drive an epithelial-to-mesenchymal transition with heightened invasiveness. Heterodimers of c-Jun and c-Fos directly bind to the Twist promoter to drive Twist gene transcription. Pharmacologic inhibition of JNK reversed the effects of N-cadherin on invasion. Thus, in addition to NF-kappa B, the JNK pathway serves as another potential target for intervention. The MAPKK that activates JNK is MKK4, which in turn is activated by the MAPKKK, TAK1. Importantly, TAK1 is the MAPKKK that activates the IKK complex in the NF-kappa B pathway inhibition of TAK1 therefore blocks both NF-kappa B and JNK activation that occurs downstream of N-cadherin and serves as a potential therapeutic target.
- Anatomy and Physiology
- Medicine and Medical Research