Introduction: Androgen deprivation therapy (ADT) is a commonly used clinical treatment for non-metastatic and metastatic hormone-sensitive prostate cancer. ADT is effective, however prolong treatment results in adverse side-effects in patients including depression, frailty, cognitive impairment and dementia. This has been confirmed in population based studies suggesting antiandrogen treatment are twice as likely to develop cognitive dysfunction and memory loss within few years of ADT. We attempt to establish a link between ADT and cognitive impairment using patient database and performed bioinformatics analysis followed by validation studies.
Methods: Gene expression profiling was performed using RNA-Seq data from Alzheimer/Parkinson patient cohort and compared with the data from advance-stage prostate cancer patients receiving neoadjuvant antiandrogen therapy before radical prostatectomy. Data of female patients were excluded from analysis. Differentially expressed genes (DEGs) were analyzed using Ingenuity knowledge database. Validation studies were performed in brain neuronal and glial cells with and without antiandrogen treatment followed by qRT-PCR.
Results: A total of 1952 DEGs in Alzheimer/Parkinson patient cohort and 101 DEGs were identified in prostate cancer patients treated with ADT. DEGs of Alzheimer/Parkinson’s patients showed overrepresentation of cytokine-cytokine receptor interaction, inflammatory cytokines, signaling by interleukins whereas alterations in the circulating lymphocyte repertoire, adaptive immune responses, regulation of cytokine production and changes in T-cell subsets were overrepresented in prostate cancer patients receiving ADT. Comparing both dataset provided a subset of 33 commonly expressed genes with changes in cytokine-cytokine signaling. Additionally, lipopolysaccharide, tumor necrosis factor and toll-like receptors were identified as upstream transcriptional regulators of these pathways. The most common expressed genes viz. CCL2, IL10, IL-6, IL1RN, LIF/LIFR were further validated by qRT-PCR exhibited higher expression in antiandrogen treated neuronal and glial cells, compared to no-ADT treatment.
Conclusions: Our findings suggest that changes in cytokine signaling under the influence of ADT in prostate cancer patients may be linked with frailty and cognitive impairment presenting new areas for diagnostic and therapeutic development in combating brain deficits.
Source of Funding: Department of Defense grant W81XWH-18-1-0618 and W81XWH-19-1-0720 to SG.