Ligand-gated ion channels as potential biomarkers for ADT-mediated cognitive decline in prostate cancer patients

Shiv Verma; Vaibhav Singh; VijayKrishna Nagampalli; Lee E Ponsky; Chiang-Shan R Li; Herta Chao; Sanjay Gupta

doi:10.1002/mc.23708

Ligand-gated ion channels as potential biomarkers for ADT-mediated cognitive decline in prostate cancer patients

Mol Carcinog. 2024 Mar 14. doi: 10.1002/mc.23708. Online ahead of print.

Authors

Shiv Verma^{1

2}, Vaibhav Singh³, VijayKrishna Nagampalli⁴, Lee E Ponsky^{1

2}, Chiang-Shan R Li⁵, Herta Chao⁶, Sanjay Gupta^{1

2

3

7

8

9}

Affiliations

¹ Department of Urology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
² The Urology Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.
³ Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
⁴ Genomic Medicine Institute, The Cleveland Clinic Foundation, Cleveland, Ohio, USA.
⁵ Department of Psychiatry and of Neuroscience, Yale University School of Medicine, New Haven, Connecticut, USA.
⁶ Department of Medicine, Yale Comprehensive Cancer Center, Yale University, New Haven, Connecticut, USA.
⁷ Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
⁸ Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
⁹ Division of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, Ohio, USA.

PMID: 38482990
DOI: 10.1002/mc.23708

Abstract

Men with prostate cancer are at increased risk of developing cognitive decline by the use of second-generation androgen signaling inhibitors. To date, reliable and sensitive biomarkers that could distinguish men at high risk of cognitive dysfunction under androgen deprivation therapy (ADT) have not been characterized. We used high-throughput transcriptional profiling utilizing human prostate cancer cell culture models mimicking ADT, biomarker selection using minimal common oncology data elements-cytoscape, and bioinformatic analyses employing Advaita® iPathwayGuide and DisGeNET for identification of disease-related gene associations. Validation analysis of genes was performed on brain neuronal and glial cells by quantitative real-time polymerase chain reaction assay. Our systematic analysis of androgen deprivation-associated genes involved multiple biological processes, including neuroactive ligand-receptor interaction, axon guidance, cytokine-cytokine receptor interaction, and metabolic and cancer signaling pathways. Genes associated with neuroreceptor ligand interaction, including gamma-aminobutyric acid (GABA) A and B receptors and nuclear core proteins, were identified as top upstream regulators. Functional enrichment and protein-protein interaction network analysis highlighted the role of ligand-gated ion channels (LGICs) and their receptors in cognitive dysfunction. Gene-disease association assigned forgetfulness, intellectual disability, visuospatial deficit, bipolar disorder, and other neurocognitive impairment with upregulation of type-1 angiotensin II receptor, brain-derived neurotrophic factor, GABA type B receptor subunit 2 (GABBR2), GABRA3, GABRA5, GABRB1, glycine receptor beta, glutamate ionotropic receptor N-methyl-D-aspartate receptor (NMDA) type subunit 1, glutamate ionotropic receptor NMDA type subunit 2D, 5-hydroxytryptamine receptor 1D, interferon beta 1, and nuclear receptor subfamily 3 group C member 1 as top differentially expressed genes. Validation studies of brain glial cells, neurons, and patients on ADT demonstrated the association of these genes with cognitive decline. Our findings highlight LGICs as potential biomarkers for ADT-mediated cognitive decline. Further validation of these biomarkers may lead to future practical clinical use.

Keywords: androgen deprivation therapy; biomarkers; brain deficits; cognitive decline; prostate cancer.

Abstract

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