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

Abstract

Kaittanis et al. show that the processing of glutamated folates by prostate-specific membrane antigen induces the activation of metabotropic glutamate receptors and initiation of PI3K–Akt signaling in prostate cancer.

Concentration‐dependent effects of dutasteride on prostate‐specific membrane antigen (PSMA) expression and uptake of 177Lu‐PSMA‐617 in LNCaP cells

“…16 Recent work suggested that the enzymatic function of PSMA is cleaving glutamate, thereby activating the glutamate driven phosphoinositide 3-kinase and subsequently the mammalian target of rapamycin (mTOR) pathway. 17 PSMA expression is known to be upregulated up to a thousand-fold higher in prostate cancer compared to normal prostate tissue. Thus, PSMA represents a potential target for imaging and therapy of prostate cancer.…”

Protocol for the PRIMARY clinical trial, a prospective, multicentre, cross‐sectional study of the additive diagnostic value of gallium‐68 prostate‐specific membrane antigen positron‐emission tomography/computed tomography to multiparametric magnetic resonance imaging in the diagnostic setting for men being investigated for prostate cancer

“…The addition of novel imaging or biomarkers may increase the detection of PCa missed by mpMRI. Prostate-specific membrane antigen (PSMA) is a cell surface transmembrane glycoprotein expressed on the cell surface by the majority of PCa cells, with its expression increasing in higher-grade malignancy [11,12]. Recently, PSMA-positron-emission tomography (PET)/CT imaging has become increasingly used in the detection of metastatic disease, especially in patients with biochemical recurrence after local treatment [13][14][15][16][17][18][19][20][21].…”

PSMA brings new flavors to PI3K signaling: A role for glutamate in prostate cancer

“…Its capacity to release glutamate form N-acetyl-l-aspartyl-glutamate (NAAG) is being explored for its therapeutic potential for brain ischemic injury and several neurodegenerative disorders. Kaittanis et al (2018) investigate the folate hydrolase activity of PSMA in prostate cancer, its biological function (uncharted thus far), and, most importantly, its potential as a therapeutic target (see figure). Kaittanis et al (2018) observe a strong positive correlation between PSMA expression, disease aggressiveness, and phosphorylation of the AKT target in prostate tumor tissue from patients with localized disease.…”

“…Kaittanis et al (2018) investigate the folate hydrolase activity of PSMA in prostate cancer, its biological function (uncharted thus far), and, most importantly, its potential as a therapeutic target (see figure). Kaittanis et al (2018) observe a strong positive correlation between PSMA expression, disease aggressiveness, and phosphorylation of the AKT target in prostate tumor tissue from patients with localized disease. Based on this evidence, they hypothesized a significant role for PSMA in modulating signaling pathways implicated in the pathogenesis of prostate cancer, specifically the PI3K-AKT-mTOR pathway.…”

“…This hypothesis is examined in detail in vitro through genetic and pharmacologic manipulation of expression and enzymatic activity of PSMA, using two different prostate cancer cell lines (LNCaP and PC3) that differ in their expression of PSMA. Taking advantage of these systems, a series of complementary experiments demonstrated PSMA-dependent activation of AKT and subsequent increased phosphorylation of downstream targets, 4EBP1 and S6, in the absence of any known intrinsic signaling properties (Kaittanis et al, 2018). Importantly, PSMA induces AKT signaling through its enzymatic activity and subsequent glutamate release.…”