N-cadherin in Prostate Cancer: Downstream Pathways and Their Translational Application for Castrate Resistant Prostate Cancer
Abstract
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. Ongoing work is focused on the biochemical pathways that link N-cadherin expression to JNK activation.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2011
- Accession Number
- ADA601952
Entities
People
- Matthew B Rettig
Organizations
- University of California, Los Angeles