Fig. 3

Molecular regulation of the phenotypic landscape by targeting α- and β-adrenoceptor signaling pathways. Top panel, Mechanistic signaling of α- adrenoceptor signaling and β-adrenoceptor eliciting effects on phenotypic EMT, apoptosis and cell proliferation. The α1-adrenoceptor signaling, activates the survival pathways NFκB and MAPK inducing transcriptional activation of growth genes (fos, myc). In response to α1-adrenoceptor pharmacologic targeting, in addition to blocking the α-adrenoceptor pathway, there is also inhibition of the TGF-β/ TGF-β receptor RI/RII/Smad signaling that induces apoptosis as well as phenotypic EMT. In response to β-adrenoceptor signaling there is activation of protein kinase A mechanism (though cAMP), promoting cell proliferation and survival via CREB activation and Bcl-2 overexpression, respectively. Lower panel, Impact of pharmacologic targeting of α1-adrenoeptor antagonists of the phenotypic interconversions (mesenchymal-EMT to epithelial-MET) within the tumor microenvironment landscape via regulation E-cadherin, IGFBP-3 and vimentin. Upon detachment from the ECM, cells unable to enter the phenotypic interconversion cycle mediated by TGF-β undergo anoikis. This provides the molecular targeting platform for α-adrenoceptor antagonists in tumor cells in the various GU organs, including the prostate and kidney