Autoantibodies directed against α1-adrenergic receptor and endothelin receptor A in patients with prostate cancer

Abstract

Background For prostate cancer, signaling pathways induced by over-boarding stimulation of G-protein coupled receptors (GPCR) such as the endothelin, α1- and β-adrenergic, muscarinic and angiotensin 1 receptors were accused to support the carcinogenesis. However, excessive receptor stimulation by physiological receptor ligands is minimized by a control system that induces receptor sensitization and down-regulation. This system is missing when so-called “functional autoantibodies” bind to the GPCR (GPCR-AAB). If GPCR-AAB were found in patients with prostate cancer, uncontrolled GPCR stimulation could make these autoantibodies an additional supporter in prostate cancer. Methods Using the bioassay of spontaneously beating cultured rat neonatal cardiomyocytes, GPCR-AAB were identified, quantified and characterized in the serum of 25 patients (aged 56–78 years, median 70 years) with prostate cancer compared to 10 male patients (aged 48–82 years, median 64) with urinary stone disorders (controls). Results Of the cancer patients, 24 (96%) and 17 (68%), respectively, carried autoantibodies directed against the α1-adrenergic receptor (α1-AAB) and endothelin receptor A (ETA-AAB). No patient was negative for both GPCR-AAB. In contrast, ETA-AAB and α1-AAB were absent in all (100%) and 9 (90%) of the 10 control patients, respectively. While α1-AAB targeted a specific epitope of the first extracellular loop of the α1-adrenergic receptor subtype A, an epitope of the second extracellular loop of the ETA receptor was identified as a target of ETA-AAB. As demonstrated in vitro, the functional activity of both autoantibodies found in prostate cancer can be neutralized by the aptamer BC007. Conclusions We hypothesized that α1-AAB and ETA-AAB, which are highly present in prostate cancer patients, could by their functional activity support carcinogenesis by excessive receptor stimulation. The in vitro demonstrated neutralization of α1- and ETA-AAB by the aptamer BC007 could open the door to complement the treatments already available for prostate cancer.

Functional autoantibodies against G-protein coupled receptors in patients with persistent Long-COVID-19 symptoms

“…This was a surprising unexpected effect. In healthy controls, which are included in many studies, these autoantibodies are only found in a small percentage [ 37 , 38 ]”.…”

Current Developments on the Role of α1-Adrenergic Receptors in Cognition, Cardioprotection, and Metabolism

“…While the autoantibody against the α 1D -AR appears antagonistic, several autoantibodies have been developed or discovered against the first or second extracellular loop of the α 1 -AR appear to be agonistic in behavior (Zhou et al, 2008;Karczewski et al, 2012;Hempel et al, 2016;Wallukat et al, 2020). While developing these autoantibodies for cardioprotective effects for the α 1A -AR may be tempting, they may not be regulated by the normal desensitization and negative feedback mechanisms common in GPCRs to turn off or wane the signal, resulting in abnormal and non-physiological signaling and proliferation (Zhou et al, 2008;Karczewski et al, 2018;Becker et al, 2019;Wallukat et al, 2020). This abnormal signaling and proliferation may account for the vascular damage that many autoantibodies also impart (Zhou et al, 2008;Karczewski et al, 2012Karczewski et al, , 2018Becker et al, 2019;Wallukat et al, 2020).…”

“…While developing these autoantibodies for cardioprotective effects for the α 1A -AR may be tempting, they may not be regulated by the normal desensitization and negative feedback mechanisms common in GPCRs to turn off or wane the signal, resulting in abnormal and non-physiological signaling and proliferation (Zhou et al, 2008;Karczewski et al, 2018;Becker et al, 2019;Wallukat et al, 2020). This abnormal signaling and proliferation may account for the vascular damage that many autoantibodies also impart (Zhou et al, 2008;Karczewski et al, 2012Karczewski et al, , 2018Becker et al, 2019;Wallukat et al, 2020). Autoantibodies against the α 1 -AR have also been associated with coronary heart disease (Thyrian et al, 2018), cardiac remodeling and dysfunction (Zhou et al, 2005;, pre-eclampsia (Ma et al, 2013), thromboangiitis obliterans (Buerger's Disease) (Klein-Weigel et al, 2014), AD and vascular dementia (Karczewski et al, 2012(Karczewski et al, , 2018Hempel et al, 2016), and prostate cancer (Wallukat et al, 2020).…”

“…This abnormal signaling and proliferation may account for the vascular damage that many autoantibodies also impart ( Zhou et al, 2008 ; Karczewski et al, 2012 , 2018 ; Becker et al, 2019 ; Wallukat et al, 2020 ). Autoantibodies against the α 1 -AR have also been associated with coronary heart disease ( Thyrian et al, 2018 ), cardiac remodeling and dysfunction ( Zhou et al, 2005 ; Li T. et al, 2017 ), pre-eclampsia ( Ma et al, 2013 ), thromboangiitis obliterans (Buerger’s Disease) ( Klein-Weigel et al, 2014 ), AD and vascular dementia ( Karczewski et al, 2012 , 2018 ; Hempel et al, 2016 ), and prostate cancer ( Wallukat et al, 2020 ). Therefore, both agonistic and antagonistic autoantibodies against the α 1 -AR subtypes would need to be thoroughly analyzed for off target effects.…”