Abstract
Preclinical and early clinical mechanistic studies of antitumor activity from the beta-adrenergic receptor (β-AR) blocker propranolol have revealed both cell signaling and immune function pathway effects. Intertumoral studies were performed using propranolol, a β1-AR selective agent (atenolol), and a β2-AR selective agent (ICI 118,551) in a preclinical in vivo model, as a step to dissect the contribution of cell signaling and CD8+ immunological effects on anticancer activity. We found that repression of β2-AR but not β1-AR signaling selectively suppressed cell viability and inhibited xenograft growth in vivo. Moreover, western blot analysis indicated that the phosphorylation levels of AKT/MEK/ERK were significantly decreased following the inhibition of β2-AR. Furthermore, propranolol was found to activate the tumor microenvironment by inducing an increased intratumoral frequency of CD8+ T cells, whereas neither selective β1 nor β2-AR blockers had a significant effect on the tumor immune microenvironment. Thus, the results of this mechanistic dissection support a predominant role of tumor cell signaling, rather than the accumulation of CD8+ T cells, as the basis for propranolol antitumor activity. KEY MESSAGES : Molecular signaling of AKT/MAPK pathway contributes to propranolol caused cancer control. CD8+ T cells in tumor microenvironment were activated upon propranolol exposure. The basis for propranolol antitumor activity was predominantly dependent on cell signaling, rather than the activation of CD8+ T cells.