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.

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

Autoimmunity Highlights ◽

10.1186/s13317-020-00136-y ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Gerd Wallukat ◽

Burkhard Jandrig ◽

Niels-Peter Becker ◽

Johann J. Wendler ◽

Peter Göttel ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Patients ◽

Functional Activity ◽

Adrenergic Receptor ◽

Receptor Subtype ◽

Endothelin Receptor ◽

Extracellular Loop ◽

Receptor Stimulation ◽

Endothelin Receptor A

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.

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

10.21203/rs.3.rs-17029/v1 ◽

2020 ◽

Author(s):

Gerd Wallukat ◽

Burkhand Jandrig ◽

Niels-Peter Becker ◽

Johann J. Wendler ◽

Peter Göttel ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Patients ◽

Functional Activity ◽

Adrenergic Receptor ◽

Receptor Subtype ◽

Endothelin Receptor ◽

Extracellular Loop ◽

Receptor Stimulation ◽

Endothelin Receptor A

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.

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Molecular mimicry between the immunodominant ribosomal protein P0 of Trypanosoma cruzi and a functional epitope on the human beta 1-adrenergic receptor.

Journal of Experimental Medicine ◽

10.1084/jem.182.1.59 ◽

1995 ◽

Vol 182 (1) ◽

pp. 59-65 ◽

Cited By ~ 108

Author(s):

I Ferrari ◽

M J Levin ◽

G Wallukat ◽

R Elies ◽

D Lebesgue ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Adrenergic Receptor ◽

Molecular Mimicry ◽

Autoimmune Response ◽

Extracellular Loop ◽

Western Blots ◽

Carboxy Terminal ◽

Ribosomal Protein P0 ◽

Positive Chronotropic Effect

Sera from chagasic patients possess antibodies recognizing the carboxy-terminal part of the ribosomal P0 protein of Trypanosoma cruzi and the second extracellular loop of the human beta 1-adrenergic receptor. Comparison of both peptides showed that they contain a pentapeptide with very high homology (AESEE in P0 and AESDE in the human beta 1-adrenergic receptor). Using a competitive immunoenzyme assay, recognition of the peptide corresponding to the second extracellular loop (H26R) was inhibited by both P0-14i (AAAESEEEDDDDDF) and P0-beta (AESEE). Concomitantly, recognition of P0-beta was inhibited with the H26R peptide. Recognition of P0 in Western blots was inhibited by P0-14i, P0-beta, and H26R, but not by a peptide corresponding to the second extracellular loop of the human beta 2-adrenergic receptor or by an unrelated peptide. Autoantibodies affinity purified with the immobilized H26R peptide were shown to exert a positive chronotropic effect in vitro on cardiomyocytes from neonatal rats. This effect was blocked by both the specific beta 1 blocker bisoprolol and the peptide P0-beta. These results unambiguously prove that T. cruzi is able to induce a functional autoimmune response against the cardiovascular human beta 1-adrenergic receptor through a molecular mimicry mechanism.

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Dual PI3 K/mTOR inhibition reduces prostate cancer bone engraftment altering tumor-induced bone remodeling

Tumor Biology ◽

10.1177/1010428318771773 ◽

2018 ◽

Vol 40 (4) ◽

pp. 101042831877177 ◽

Cited By ~ 2

Author(s):

Andrea Mancini ◽

Alessandro Colapietro ◽

Simona Pompili ◽

Andrea Del Fattore ◽

Simona Delle Monache ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Patients ◽

Therapeutic Potential ◽

Disease Free Survival ◽

Bone Lesions ◽

Metastatic Progression ◽

Mtor Inhibition ◽

Osteoblast Activity

Morbidity in advanced prostate cancer patients is largely associated with bone metastatic events. The development of novel therapeutic strategies is imperative in order to effectively treat this incurable stage of the malignancy. In this context, Akt signaling pathway represents a promising therapeutic target able to counteract biochemical recurrence and metastatic progression in prostate cancer. We explored the therapeutic potential of a novel dual PI3 K/mTOR inhibitor, X480, to inhibit tumor growth and bone colonization using different in vivo prostate cancer models including the subcutaneous injection of aggressive and bone metastatic (PC3) and non-bone metastatic (22rv1) cell lines and preclinical models known to generate bone lesions. We observed that X480 both inhibited the primary growth of subcutaneous tumors generated by PC3 and 22rv1 cells and reduced bone spreading of PCb2, a high osteotropic PC3 cell derivative. In metastatic bone, X480 inhibited significantly the growth and osteolytic activity of PC3 cells as observed by intratibial injection model. X480 also increased the bone disease-free survival compared to untreated animals. In vitro experiments demonstrated that X480 was effective in counteracting osteoclastogenesis whereas it stimulated osteoblast activity. Our report provides novel information on the potential activity of PI3 K/Akt inhibitors on the formation and progression of prostate cancer bone metastases and supports a biological rationale for the use of these inhibitors in castrate-resistant prostate cancer patients at high risk of developing clinically evident bone lesions.

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Adrenergic activation of glycogen phosphorylase in primary culture diabetic cardiomyocytes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1992.262.3.h649 ◽

1992 ◽

Vol 262 (3) ◽

pp. H649-H653 ◽

Cited By ~ 3

Author(s):

J. A. Buczek-Thomas ◽

S. R. Jaspers ◽

T. B. Miller

Keyword(s):

Hypersensitive Response ◽

Adrenergic Receptor ◽

Glycogen Phosphorylase ◽

Receptor Activation ◽

Receptor Stimulation ◽

Beta Adrenergic ◽

Rat Cardiomyocytes ◽

Adult Rat ◽

Adrenergic Activation

The basis of catecholamine-induced activation of glycogen phosphorylase was investigated in adult rat cardiomyocytes isolated from normal and alloxan-diabetic animals. Cells derived from diabetic animals exhibited a hypersensitive response to epinephrine stimulation that was apparent 3 h after cell isolation and was further enhanced on maintenance of the myocytes in culture for 24 h. Normal cells initially lacked the hypersensitive response to epinephrine stimulation, although on maintenance of these cells in culture for 24 h, the hypersensitive response was acquired in vitro. To assess alpha- and beta-adrenergic mediation of the response, normal and diabetic cardiomyocytes were incubated with propranolol, a beta-blocker, before direct alpha 1-receptor stimulation with phenylephrine. Both normal and diabetic myocytes failed to undergo activation of phosphorylase in 3- or 24-h cell cultures. In addition, the effects of epinephrine on phosphorylase activation were completely inhibited by propranolol, whereas prazosin, an alpha-blocker, was unsuccessful. The present data suggest that the hypersensitive response of glycogen phosphorylase in normal and diabetic cardiomyocytes is solely mediated through beta-adrenergic receptor activation.

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EXPRESSION OF ENDOTHELIN RECEPTOR A ASSOCIATED WITH PROSTATE CANCER PROGRESSION

The Journal of Urology ◽

10.1097/00005392-200103000-00082 ◽

2001 ◽

pp. 1033-1036 ◽

Cited By ~ 1

Author(s):

KAZUO GOHJI ◽

SOHEI KITAZAWA ◽

HIROSHI TAMADA ◽

YOJI KATSUOKA ◽

MOTOWO NAKAJIMA

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Endothelin Receptor ◽

Prostate Cancer Progression ◽

Endothelin Receptor A

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In vivo versus in vitro individual radiosensitivity analysed in healthy donors and in prostate cancer patients with and without severe side effects after radiotherapy

International Journal of Radiation Biology ◽

10.3109/09553002.2012.666002 ◽

2012 ◽

Vol 88 (5) ◽

pp. 405-413 ◽

Cited By ~ 32

Author(s):

Kinga Brzozowska ◽

Michael Pinkawa ◽

Michael J. Eble ◽

Wolfgang-Ullrich Müller ◽

Andrzej Wojcik ◽

...

Keyword(s):

Prostate Cancer ◽

Side Effects ◽

Cancer Patients ◽

Individual Radiosensitivity ◽

Healthy Donors

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The Effects of Serum from Prostate Cancer Patients with Elevated Body Mass Index on Prostate Cancer Cells in Vitro

Lipid Insights ◽

10.4137/lpi.s23135 ◽

2015 ◽

Vol 8 ◽

pp. LPI.S23135

Author(s):

Benjamin C. Mora ◽

Neil E. Fleshner ◽

Laurence H. Klotz ◽

Vasundara Venkateswaran

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Cell Migration ◽

Cancer Patients ◽

Migration And Invasion ◽

Obese Patients ◽

Control Groups ◽

Necrosis Factor Alpha ◽

Pc3 Cells

We examined whether serum from obese, compared to non-obese, PCa (prostate cancer) patients creates a growth-enhancing tumor micro-environment in vitro. Serum from 80 subjects was divided into four groups: normal weight men with and without PCa and overweight/obese men with and without PCa. Cell proliferation, migration, and invasion were measured in LNCaP, and PC3 cells treated with patient serum were obtained from the above groups. The results reveal that proliferation of LNCaP cells was significantly ( P = 0.05) greater with serum from non-obese (mean = 1.26 ± 0.20) compared to that from obese patients (mean = 1.16 ± 0.19). Serum from obese PCa patients compared to non-obese PCa patients induced significantly greater amounts of cell migration ( P < 0.01) in PC3 cells. Serum from obese patients induced significantly ( P < 0.01) lower amounts of cell invasion (mean = 8.2 ± 4.5) compared to non-obese patients (mean = 18.1 ± 5.0) when treated on PC3 cells. Serum TNF-α (tumor necrosis factor alpha) levels correlated with LNCaP cell proliferation in vitro in non-obese PCa ( P < 0.01) and non-obese control groups ( P = 0.05). All statistical calculations controlled for age, since the PCa patient groups were significantly older than the control groups ( P < 0.01). In conclusion, serum from obese PCa patients induced greater PCa cell migration and lower cell proliferation and invasion in vitro.

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