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.
Highlights
Prostate cancer is the most common cancer diagnosed in men
Expression of prostate-specific membrane antigen (PSMA) in patients with prostate cancer correlates with elevated mammalian target of rapamycin (mTOR) signaling Because PSMA (FOLH1) has been identified as a promising marker for prostate cancer, we investigated whether its expression is reflective of disease state in cancer patients
Given the clear correlation of PSMA with disease aggressiveness, we examined whether overexpression of PSMA correlates with alterations in major oncogenic signaling pathways
Summary
It is estimated that one in every seven men will be diagnosed with the disease during his lifetime. The medical community utilizes early diagnostic tools and new therapeutic approaches for localized disease, the National Institutes of Health’s Surveillance, Epidemiology, and End Results Program (SEER) estimates that 26,730 deaths will be attributed to metastatic prostate cancer in 2017. PSMA (FOLH1, GCPII) is normally expressed in the proximal renal tubules and duodenum, where it plays a major role in the processing and uptake of dietary folates, and in the brain, where it processes N-acetyl-l-aspartyl-l-glutamate (NAAG) to modulate the output of glutamate signaling transduced via the metabotropic glutamate receptor (mGluR) pathway (Rajasekaran et al, 2005; Rahn et al, 2012a). PSMA-targeted radiotherapy in metastatic castration-resistant prostate cancer was recently able to confer
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