β-Adrenergic Receptor Signaling in Prostate Cancer

Abstract

Enhanced sympathetic signaling, often associated with obesity and chronic stress, is increasingly acknowledged as a contributor to cancer aggressiveness. In prostate cancer, intact sympathetic nerves are critical for tumor formation, and sympathectomy induces apoptosis and blocks tumor growth. Perineural invasion, involving enrichment of intra-prostatic nerves, is frequently observed in prostate cancer and is associated with poor prognosis. β2-adrenergic receptor (ADRB2), the most abundant receptor for sympathetic signals in prostate luminal cells, has been shown to regulate trans-differentiation of cancer cells to neuroendocrine-like cells and to affect apoptosis, angiogenesis, epithelial-mesenchymal transition, migration, and metastasis. Epidemiologic studies have shown that use of β-blockers, inhibiting β-adrenergic receptor activity, is associated with reduced prostate cancer-specific mortality. In this review, we aim to present an overview on how β-adrenergic receptor and its downstream signaling cascade influence the development of aggressive prostate cancer, primarily through regulating neuroendocrine differentiation.

Keywords: ADRB2; angiogenesis; apoptosis; metastasis; neuroendocrine differentiation; prostate cancer; β-adrenergic receptor; β-blocker.

Figure 1

The ADRB2 signaling pathways in prostate cancer. Ligand binding to ADRB2 increases the intracellular level of cAMP, which activates cAMP-dependent protein kinase (PKA). PKA may either directly or through PAK4 stimulate CREB activity and thereby induce the expression of ENO2 and BCL2. PKA can also directly or indirectly via PAK4 or Rap1 inhibit RhoA and ROCK activities and thereby induce neurite outgrowth. Finally, VEGF expression is up-regulated by adrenergic stimulation via PI3K/AKT/p70S6K mediated activation of HIF-1α.

Figure 2

Hypothetical model of how β₂-adrenergic signaling may promote progression of prostate cancer. In summary, we hypothesize that ADRB2s expressed on luminal cells are activated by catecholamines, which are secreted by nerves and transported through blood vessels in response to stress. Catecholamines are possibly also secreted by proximal chromaffin-like cells and macrophages (not shown) that also can produce epinephrine and norepinephrine, respectively. In addition, ADRB2s expressed on stromal cells are activated by sympathetic stimuli. Upon ligand-binding, the expression of anti-apoptotic and pro-angiogenic factors is increased and a number of cancer cells undergo trans-differentiation to neuroendocrine-like cells. Together this will favor tumor growth. Angiogenesis and neurogenesis are closely linked (132) and sympathetic activation may stimulate perineural invasion through chemotaxis. In general, chronic ADRB2 activation down-regulates the ADRB2-level, leading to de-differentiation and epithelial–mesenchymal transition, with a subsequent increase in the migratory and invasive potential of the cells. Cancer cells expressing low levels of ADRB2 will thereby follow the nerves and blood vessels to metastatic sites.

Figure 3

Effects of ADRB2 on tumor characteristics in cell lines, mouse models, and human prostate cancer. The effects of β-blockers on the different characteristics in each model system is also shown.