ADRB2-Targeting Therapies for Prostate Cancer

Abstract

There is accumulating evidence that β-2 adrenergic receptor (ADRB2) signaling contributes to the progression and therapy resistance of prostate cancer, whereas availability of clinically tested β-blocker propranolol makes this pathway especially attractive as potential therapeutic target. Yet even in tumors with active ADRB2 signaling propranolol may be ineffective. Inhibition of apoptosis is one of the major mechanisms by which activation of ADRB2 contributes to prostate cancer pathophysiology. The signaling network that controls apoptosis in prostate tumors is highly redundant, with several signaling pathways targeting a few critical apoptosis regulatory molecules. Therefore, a comprehensive analysis of ADRB2 signaling in the context of other signaling mechanisms is necessary to identify patients who will benefit from propranolol therapy. This review discusses how information on the antiapoptotic mechanisms activated by ADRB2 can guide clinical trials of ADRB2 antagonist propranolol as potential life-extending therapy for prostate cancer. To select patients for clinical trials of propranolol three classes of biomarkers are proposed. First, biomarkers of ADRB2/cAMP-dependent protein kinase (PKA) pathway activation; second, biomarkers that inform about activation of other signaling pathways unrelated to ADRB2; third, apoptosis regulatory molecules controlled by ADRB2 signaling and other survival signaling pathways.

Keywords: BCL-2-associated death promoter (BAD); apoptosis; cAMP-dependent protein kinase (PKA); clinical trial; myeloid cell leukemia 1 (MCL-1); propranolol; prostate cancer; β-2 adrenergic receptor (ADRB2).

Figure 1

ADRB2 signaling in prostate cancer. (A) epinephrine (Epi) and norepinephrine (NE) from circulation and secreted locally by sympathetic nerves, neurodifferentiated prostate cancer cells and macrophages activate anti-apoptotic signaling in prostate cancer cells and stimulate angiogenesis and invasion; (B) Activation of ADRB2 signaling (that can be inhibited by propranolol) induces phosphorylation of PKA substrates pS133CREB, pS157VASP, p75BAD and increases expression of myeloid cell leukemia 1 (MCL-1). Dephosphorylations of vasodilator-stimulated phosphoprotein (VASP) and cAMP response element binding protein (CREB) reflect inactivation of β-2 adrenergic receptor/cAMP-dependent protein kinase (ADRB2/PKA) signaling pathway by propranolol, whereas decreased levels of MCL-1 and p75BAD predict whether propranolol will sensitize prostate cells to apoptosis.

Figure 2

Anti-apoptotic signaling pathways in prostate cancer converge on MCL-1 and BAD. (A) Epi and NE activate ADRB2/cAMP/PKA signaling cascade that in turn phosphorylates S133CREB, S157VASP, S75BAD and increases MCL-1 expression; (B) Other Gα_s coupled GPCRs can activate cAMP/PKA and induce similar pattern of phosphorylated PKA substrates as ADRB2 activation; (C) GPCR-independent signaling pathways (Receptor tyrosine kinases, Ras; PI3K/AKT) can induce S75BAD phosphorylation and increase expression of MCL-1; (D) Expression of BclXL and/or loss of NOXA, BIM, PUMA can increase apoptosis threshold without changing BAD phosphorylation or MCL-1 levels.