Identification of alternative protein targets of glutamate-ureido-lysine associated with PSMA tracer uptake in prostate cancer cells Journal Article
| Authors: | Bakht, M. K.; Hayward, J. J.; Shahbazi-Raz, F.; Skubal, M.; Tamura, R.; Stringer, K. F.; Meister, D.; Venkadakrishnan, V. B.; Xue, H.; Pillon, A.; Stover, M.; Tronchin, A.; Fifield, B. A.; Mader, L.; Ku, S. Y.; Cheon, G. J.; Kang, K. W.; Wang, Y.; Dong, X.; Beltran, H.; Grimm, J.; Porter, L. A.; Trant, J. F. |
| Article Title: | Identification of alternative protein targets of glutamate-ureido-lysine associated with PSMA tracer uptake in prostate cancer cells |
| 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. © 2022 National Academy of Sciences. All rights reserved. |
| Keywords: | molecular imaging; prostate cancer; pet; psma; glutamate-ureido-lysine |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 119 |
| Issue: | 4 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2022-01-25 |
| Start Page: | e2025710119 |
| Language: | English |
| DOI: | 10.1073/pnas.2025710119 |
| PROVIDER: | scopus |
| PMCID: | PMC8795759 |
| PUBMED: | 35064078 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 February 2022 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work