beta adrenergic receptor modulated signaling in glioma models: promoting beta adrenergic receptor-beta arrestin scaffold-mediated activation of extracellular-regulated kinase 1/2 may prove to be a panacea in the treatment of intracranial and spinal malignancy and extra-neuraxial carcinoma

摘要

Neoplastically transformed astrocytes express functionally active cell surface beta adrenergic receptors (beta ARs). Treatment of glioma models in vitro and in vivo with beta adrenergic agonists variably amplifies or attenuates cellular proliferation. In the majority of in vivo models, beta adrenergic agonists generally reduce cellular proliferation. However, treatment with beta adrenergic agonists consistently reduces tumor cell invasive potential, angiogenesis, and metastasis. beta adrenergic agonists induced decreases of invasive potential are chiefly mediated through reductions in the expression of matrix metalloproteinases types 2 and 9. Treatment with beta adrenergic agonists also clearly reduce tumoral neoangiogenesis, which may represent a putatively useful mechanism to adjuvantly amplify the effects of bevacizumab. Bevacizumab is a monoclonal antibody targeting the vascular endothelial growth factor receptor. We may accordingly designate beta agonists to represent an enhancer of bevacizumab. The antiangiogenic effects of beta adrenergic agonists may thus effectively render an otherwise borderline effective therapy to generate significant enhancement in clinical outcomes. beta adrenergic agonists upregulate expression of the major histocompatibility class II DR alpha gene, effectively potentiating the immunogenicity of tumor cells to tumor surveillance mechanisms. Authors have also demonstrated crossmodal modulation of signaling events downstream from the beta adrenergic cell surface receptor and microtubular polymerization and depolymerization. Complex effects and desensitization mechanisms of the beta adrenergic signaling may putatively represent promising therapeutic targets. Constant stimulation of the beta adrenergic receptor induces its phosphorylation by beta adrenergic receptor kinase (beta ARK), rendering it a suitable substrate for alternate binding by beta arrestins 1 or 2. The binding of a beta arrestin to beta ARK phosphorylated beta AR promotes receptor mediated internalization and downregulation of cell surface receptor and contemporaneously generates a cell surface scaffold at the beta AR. The scaffold mediated activation of extracellular regulated kinase 1/2, compared with protein kinase A mediated activation, preferentially favors cytosolic retention of ERK1/2 and blunting of nuclear translocation and ensuant pro-transcriptional activity. Thus, beta AR desensitization and consequent scaffold assembly effectively retains the cytosolic homeostatic functions of ERK1/2 while inhibiting its pro-proliferative effects. We suggest these mechanisms specifically will prove quite promising in developing primary and adjuvant therapies mitigating glioma growth, angiogenesis, invasive potential, and angiogenesis. We suggest generating compounds and targeted mutations of the beta adrenergic receptor favoring beta arrestin binding and scaffold facilitated activation of ERK1/2 may hold potential promise and therapeutic benefit in adjuvantly treating most or all cancers. We hope our discussion will generate fruitful research endeavors seeking to exploit these mechanisms.