Identification of alternative protein targets of glutamate-ureido-lysine associated with PSMA tracer uptake in prostate cancer cells.
Martin K BakhtJohn J HaywardFarsheed Shahbazi-RazMagdalena SkubalRyo TamuraKeith F StringerDaniel MeisterVaradha Balaji VenkadakrishnanHui XueAdam PillonMathew StoverAdam TronchinBre-Anne FifieldLavleen K MaderSheng-Yu KuGi Jeong CheonKeon-Wook KangYuzhuo Z WangXuesen DongHimisha BeltranJan GrimmLisa A PorterJohn F TrantPublished in: Proceedings of the National Academy of Sciences of the United States of America (2022)
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.
Keyphrases
- pet ct
- pet imaging
- poor prognosis
- prostate cancer
- positron emission tomography
- cell cycle
- long non coding rna
- squamous cell carcinoma
- small molecule
- computed tomography
- radical prostatectomy
- benign prostatic hyperplasia
- cardiovascular disease
- risk factors
- cell proliferation
- fluorescence imaging
- binding protein
- quantum dots
- single molecule
- climate change
- current status
- human health