Figure 7. A proposed model for PDGF-BB regulation of Mcl-1 expression in PCa cells.

The engagement of PDGF-BB to PDGFR dimers activates the c-Abl-p68 cascade, which subsequently stablizes β-catenin and promotes its nuclear translocation. In the nucleus, interaction between β-catenin and HIF-1α increases the binding of HIF-1α to the HRE site within Mcl-1 promoter, thereby activating the transcription of Mcl-1 gene. Upregulation of Mcl-1 antagonizes apoptotic signals and confers survival advantages to metastatic PCa cells. Furthermore, tumor-derived and locally expressed PDGF may mediate the interactions between PCa and bone microenvironment. Co-targeting the PDGF signaling in PCa cells (autocrine) and microenvironment (paracrine) could provide a new strategy to disrupt the “vicious cycle” and efficaciously treat metastatic PCa.