Cognition-mediated transcriptomic signature associated with androgen deprivation therapy in prostate cancer

Abstract Androgen deprivation therapy (ADT) is the mainstay treatment for non-metastatic and metastatic hormone-sensitive prostate cancer. Long-term ADT treatment results in adverse side-effects in patients including depression, memory loss, cognitive decline, and dementia. We aimed to identify critical molecules that could provide link between brain-related changes and pathological mechanisms responsible for cognitive decline in prostate cancer patients on ADT protocol. For these studies, gene expression data (GSE150807 and GSE151083) of human prostate cancer cells exposed to enzalutamide emulating ADT protocol was used to identify differential expression of genes at the transcript level. RNA sequencing analysis identified 9409 and 7757 differentially expressed genes (DEGs) in LNCaP and C4-2B enzalutamide exposed cells at p-value < 0.0005 and FDR< 0.05. In both cell lines, neuronal receptor signaling pathway was significantly overrepresented at 0.05 FDR-adjusted p-value (q-value). The genes associated with neuronal receptor signaling pathway belong to the ligand-gated ion channel and G-protein coupled receptors. Validation studies using brain glial cells treated with enzalutamide showed significant upregulation (p-value 0.001) of GABRB1, GABRA3, GABBR2 (GABA receptors/ligand-gated ion channel), BDNF (brain-derived neurotrophic factor), IFNB1 (interferon beta 1), NR3C1 (nuclear receptor subfamily 3 group c member/glucocorticoid receptor), ATGR1 (type-1 angiotensin II receptor), GRIN1 (glutamate ionotropic receptor NMDA type submit 1/ligated-gated ion channel), GRIN2D (glutamate ionotropic receptor NMDA type submit 2D/ligated-gated ion channel). In brain neuronal cells, enzalutamide exposure resulted in increased expression of NR3C1 whereas GABA/ligand-gated ion channel and others were downregulated and/or statistically non-significant. Further analysis using DisGenET (cytoscape) highlighted ATGR1, GABRB1, GRIN1, GRIN2D, and NR3C1 association with neuronal diseases including cognition disorder, forgetfulness, depressive mood, and others. The results of our study provide the first proof of evidence linking cognitive decline, depression, memory loss, and other neurological disorder more likely to develop in prostate cancer patients undergoing long-term androgen deprivation therapy. Citation Format: Shiv Shankar Verma, Eswar Shankar, Vaibhav Singh, Vijay Krishna, Sanjay Gupta. Cognition-mediated transcriptomic signature associated with androgen deprivation therapy in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1451.