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

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

Authors:	Kaittanis, C.; Andreou, C.; Hieronymus, H.; Mao, N.; Foss, C. A.; Eiber, M.; Weirich, G.; Panchal, P.; Gopalan, A.; Zurita, J.; Achilefu, S.; Chiosis, G.; Ponomarev, V.; Schwaiger, M.; Carver, B. S.; Pomper, M. G.; Grimm, J.
Article Title:	Prostate-specific membrane antigen cleavage of vitamin B9 stimulates oncogenic signaling through metabotropic glutamate receptors
Abstract:	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. © 2018 Kaittanis et al.
Keywords:	controlled study; protein expression; protein phosphorylation; unclassified drug; human cell; disease course; nonhuman; cancer patient; nuclear magnetic resonance imaging; positron emission tomography; animal cell; mouse; tumor volume; animal experiment; animal model; tumor regression; tumor xenograft; enzyme activity; prostate cancer; prostate specific membrane antigen; mammalian target of rapamycin; tissue microarray; biochemical recurrence; mtor signaling; nitric oxide synthase; vitamin b9; gamma glutamyl hydrolase; transcription factor runx2; pi3k/akt signaling; vitamin b group; phospholipase c; epifluorescence microscopy; enzalutamide; human; male; priority journal; article; lncap cell line; 22rv1 cell line; metabotropic receptor; pc-3m cell line
Journal Title:	Journal of Experimental Medicine
Volume:	215
Issue:	1
ISSN:	0022-1007
Publisher:	Rockefeller University Press
Date Published:	2018-01-01
Start Page:	159
End Page:	175
Language:	English
DOI:	10.1084/jem.20171052
PROVIDER:	scopus
PMCID:	PMC5748857
PUBMED:	29141866
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85039969097&doi=10.1084%2fjem.20171052&partnerID=40&md5=fda4d8ae73677ddd71bf6989a6fddd0c
Notes:	Article -- Export Date: 1 February 2018 -- Source: Scopus