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

Authors

Martin K. Bakht, University of Windsor
John J. Hayward, University of Windsor
Farsheed Shahbazi-Raz, University of Windsor
Magdalena Skubal, Memorial Sloan-Kettering Cancer Center
Ryo Tamura, Memorial Sloan-Kettering Cancer Center
Keith F. Stringer, University of Windsor
Daniel Meister, University of Windsor
Varadha Balaji Venkadakrishnan, Dana-Farber Cancer Institute
Hui Xue, The University of British Columbia
Adam Pillon, University of Windsor
Mathew Stover, University of Windsor
Adam Tronchin, University of Windsor
Bre Anne Fifield, University of Windsor
Lavleen Mader, University of Windsor
Sheng Yu Ku, Dana-Farber Cancer Institute
Gi Jeong Cheon, Seoul National University College of Medicine
Keon Wook Kang, Seoul National University College of Medicine
Yuzhuo Wang, The University of British Columbia
Xuesen Dong, The University of British Columbia
Himisha Beltran, Dana-Farber Cancer Institute
Jan Grimm, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center
Lis A. Porter, Department of Biomedical Sciences, University of Windsor
John F. Trant, Department of Chemistry and Biochemistry, University of Windsor

Document Type

Article

Publication Date

1-25-2022

Publication Title

Proceedings of the National Academy of Sciences of the United States of America

Volume

119

Issue

4

Keywords

Glutamate-ureido-lysine, Molecular imaging, PET, Prostate cancer, PSMA

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.

DOI

10.1073/pnas.2025710119

ISSN

00278424

E-ISSN

10916490

Recommended Citation

Bakht, Martin K.; Hayward, John J.; Shahbazi-Raz, Farsheed; Skubal, Magdalena; Tamura, Ryo; Stringer, Keith F.; Meister, Daniel; Venkadakrishnan, Varadha Balaji; Xue, Hui; Pillon, Adam; Stover, Mathew; Tronchin, Adam; Fifield, Bre Anne; Mader, Lavleen; Ku, Sheng Yu; Cheon, Gi Jeong; Kang, Keon Wook; Wang, Yuzhuo; Dong, Xuesen; Beltran, Himisha; Grimm, Jan; Porter, Lis A.; and Trant, John F.. (2022). Identification of alternative protein targets of glutamate-ureido-lysine associated with PSMA tracer uptake in prostate cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 119 (4).
https://scholar.uwindsor.ca/chemistrybiochemistrypub/168

PubMed ID

35064078