Identification of alternative protein targets of glutamate-ureido-lysine associated with PSMA tracer uptake in prostate cancer cells
| Autor: | Martin K. Bakht, John J. Hayward, Farsheed Shahbazi-Raz, Magdalena Skubal, Ryo Tamura, Keith F. Stringer, Daniel Meister, Varadha Balaji Venkadakrishnan, Hui Xue, Adam Pillon, Mathew Stover, Adam Tronchin, Bre-Anne Fifield, Lavleen Mader, Sheng-Yu Ku, Gi Jeong Cheon, Keon Wook Kang, Yuzhuo Wang, Xuesen Dong, Himisha Beltran, Jan Grimm, Lisa A. Porter, John F. Trant |
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| Rok vydání: | 2022 |
| Předmět: |
Prostate cancer
Multidisciplinary Molecular imaging Biological Sciences urologic and male genital diseases prostate cancer molecular imaging Biochemistry glutamate-ureido-lysine Glutamate-ureido-lysine Chemistry Biophysics and Computational Biology PET Physical Sciences PSMA Biochemistry Biophysics and Structural Biology |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America Chemistry and Biochemistry Publications |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Significance Glutamate-ureido-lysine (GUL) probes are specific for prostate-specific membrane antigen (PSMA), overexpressed by most prostate cancers. This antigen can be lost as the cancer progresses. Recent reports have indicated that GUL probes can still identify these PSMA-negative tumors, indicating that the expression of alternative PSMA-like proteins may change during disease progression. In this study we identified two such candidate protein targets, NAALADaseL and mGluR8, by using a combined computational chemistry, data mining, molecular biology, radiochemistry, and synthetic chemistry approach. This work consequently prepares the groundwork for developing specific probes that can identify this progression, indicates directions for neuroendocrine prostate cancer research, and highlights the utility of a multidisciplinary approach for the rapid identification of unidentified proteins interacting with diagnostic probes. 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. |
| Databáze: | OpenAIRE |
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