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.

Activation of β-adrenergic receptor promotes cellular proliferation in human glioblastoma

“…In previous decades, numerous studies have demonstrated that β-ARs may also regulate different processes of cancer initiation and progression, through activating the classical cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway and mitogen-activated protein kinases (MAPK) pathway (13,14). For example, in pancreatic ductal adenocarcinomas cells, it has been suggested that β-AR agonists promote cell growth by activating signaling via adenylyl cyclase (AC) and its downstream effectors cAMP, PKA and nuclear transcription factor cAMP-responsive element-binding protein (15).…”

Triiodothyronine Attenuates Prostate Cancer Progression Mediated by β-Adrenergic Stimulation

“…These data were not surprising, since robust studies show that sympathetic input (via β-adrenergic receptors) is crucial for the initiation and progression of prostate and hepatic cancer (12,36,37). The decrease in tumor growth by ISO was associated with an increased expression of genes related to cell arrest (p27 kip ), NE differentiation (survivin, CgA and NSE) and cell invasion (VEGF, uPA and MMP-9) (8,(38)(39)(40)(41)(42)(43).…”

“…PKA directly induces the inactivation of an apoptotic factor (phosphorylation of BAD) (9), and it indirectly stimulates VEGF secretion (PI3K/AKT/hypoxia inducible factor-1α [HIF-1α]) (48) and neurite outgrowth by cytoskeleton rearrangements (inhibition of Ras homolog gene family A [RhoA]/Rho-associated protein kinase [ROCK]) (49). PKA also induces the phosphorylation of CREB and the expression of cell survival factors (Bcl-2), metalloproteases and NE peptides (NSE, CgA, SYP, neurotensin and so on) (8,9,36). Along this line, our data confirm an association between acquisition of the NE phenotype and high levels of pCREB in ISO-treated LNCaP cells.…”

Molecularly targeted radiosensitization chances towards gene aberration-due organ confined/regionally advanced prostate cancer radioresistance

“…Among further developments of customized radiosensitizers, just those molecularly targeting the identified PCa cell radioresistance-linked individual gene aberrations will enhance the PCa radiation therapy lasting effectiveness (1)(2)(3)(4)(5)(6)(7)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19).…”

“…It is emerging from a recent study (14) that the chronic stress/obesity-dependent norepinephrine or epinephrine-triggered enhancement of sympathetic sygnaling, mainly involving prostate luminal cell β 2 adrenergic receptors, may support, together with PCa cell neuroendocrine transdifferentiation, the Bcl 2-mediated antiapoptotic effects and the radioresistance onset. It follows that the use of β 2 adrenergic receptor antagonists -among which ICI 118,551 hydrochloride, C 17 H 27 NO 2 HCL -could play a customized role to overcome the PCa radioresistance, though ionizing radiation, as well as the androgen deprivation, may facilitate the PCa cell neuroendocrine transdifferentiation.…”