Identification of alternative protein targets of glutamate-ureido-lysine associated with PSMA tracer uptake in prostate cancer cells

Proc Natl Acad Sci U S A. 2022 Jan 25;119(4):e2025710119. doi: 10.1073/pnas.2025710119.

Abstract

Prostate-specific membrane antigen (PSMA) is highly overexpressed in most prostate cancers and is clinically visualized using PSMA-specific probes incorporating glutamate-ureido-lysine (GUL). PSMA is effectively absent from certain high-mortality, treatment-resistant subsets of prostate cancers, such as neuroendocrine prostate cancer (NEPC); however, GUL-based PSMA tracers are still reported to have the potential to identify NEPC metastatic tumors. These probes may bind unknown proteins associated with PSMA-suppressed cancers. We have identified the up-regulation of PSMA-like aminopeptidase NAALADaseL and the metabotropic glutamate receptors (mGluRs) in PSMA-suppressed prostate cancers and find that their expression levels inversely correlate with PSMA expression and are associated with GUL-based radiotracer uptake. Furthermore, we identify that NAALADaseL and mGluR expression correlates with a unique cell cycle signature. This provides an opportunity for the future study of the biology of NEPC and potential therapeutic directions. Computationally predicting that GUL-based probes bind well to these targets, we designed and synthesized a fluorescent PSMA tracer to investigate these proteins in vitro, where it shows excellent affinity for PSMA, NAALADaseL, and specific mGluRs associated with poor prognosis.

Keywords: PET; PSMA; glutamate-ureido-lysine; molecular imaging; prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Surface / chemistry
  • Antigens, Surface / metabolism*
  • Binding Sites
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Disease Models, Animal
  • Disease Progression
  • Fluorescent Antibody Technique
  • Fluorescent Dyes / chemical synthesis
  • Fluorescent Dyes / chemistry
  • Gene Expression
  • Glutamate Carboxypeptidase II / chemistry
  • Glutamate Carboxypeptidase II / metabolism*
  • Glutamates* / chemistry
  • Humans
  • Immunohistochemistry
  • Lysine* / chemistry
  • Male
  • Mice
  • Models, Molecular
  • Molecular Conformation
  • Molecular Imaging / methods
  • Molecular Probes* / chemistry
  • Prostatic Neoplasms / diagnosis*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Protein Binding
  • Receptors, Kainic Acid / genetics
  • Receptors, Kainic Acid / metabolism
  • Structure-Activity Relationship
  • Urea* / analogs & derivatives
  • Urea* / chemistry

Substances

  • Antigens, Surface
  • Cell Cycle Proteins
  • Fluorescent Dyes
  • Glutamates
  • Molecular Probes
  • Receptors, Kainic Acid
  • Urea
  • FOLH1 protein, human
  • Glutamate Carboxypeptidase II
  • Lysine