426: Potential Signal Generation Through Metabotropic Glutamate Receptors by Prostate Specific Membrane Antigen

2004 ◽  
Vol 171 (4S) ◽  
pp. 112-112
Author(s):  
Aaron Milbank ◽  
Mike Aleman ◽  
Kelley Harsch ◽  
Nick Detore ◽  
Eric A. Klein ◽  
...  
Keyword(s):  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Signal Generation ◽  
Prostate Specific Membrane Antigen ◽  
Metabotropic Glutamate ◽  
Potential Signal ◽  
Specific Membrane

scholarly journals Prostate-specific membrane antigen cleavage of vitamin B9 stimulates oncogenic signaling through metabotropic glutamate receptors

2017 ◽  
Vol 215 (1) ◽  
pp. 159-175 ◽  
Author(s):  
Charalambos Kaittanis ◽  
Chrysafis Andreou ◽  
Haley Hieronymus ◽  
Ninghui Mao ◽  
Catherine A. Foss ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Tumor Regression ◽  
Prostate Specific Membrane Antigen ◽  
Oncogenic Signaling ◽  
Metabotropic Glutamate ◽  
Vitamin B9 ◽  
Specific Membrane

Prostate-specific membrane antigen (PSMA) or folate hydrolase 1 (FOLH1) is highly expressed on prostate cancer. Its expression correlates inversely with survival and increases with tumor grade. However, the biological role of PSMA has not been explored, and its role in prostate cancer remained elusive. Filling this gap, we demonstrate that in prostate cancer, PSMA initiates signaling upstream of PI3K through G protein–coupled receptors, specifically via the metabotropic glutamate receptor (mGluR). PSMA’s carboxypeptidase activity releases glutamate from vitamin B9 and other glutamated substrates, which activate mGluR I. Activated mGluR I subsequently induces activation of phosphoinositide 3-kinase (PI3K) through phosphorylation of p110β independent of PTEN loss. The p110β isoform of PI3K plays a particularly important role in the pathogenesis of prostate cancer, but the origin of its activation was so far unknown. PSMA expression correlated with PI3K–Akt signaling in cells, animal models, and patients. We interrogated the activity of the PSMA–PI3K axis through positron emission tomography and magnetic resonance imaging. Inhibition of PSMA in preclinical models inhibited PI3K signaling and promoted tumor regression. Our data present a novel oncogenic signaling role of PSMA that can be exploited for therapy and interrogated with imaging.

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