The role of TRAIL in cancer-related fatigue following radiation therapy
Friday, September 16, 2016 — Poster Session IV
- LN Saligan
Chronic fatigue is one of the most common and debilitating side effects of cancer and cancer treatment, and yet its etiology remains elusive. The goal of this study is to understand the underlying inflammatory mechanism and identify co-occurring symptoms of chronic fatigue in non-metastatic prostate cancer men following radiation therapy (RT) completion. The initial investigation included 40 men scheduled to receive RT at the National Institutes of Health, Bethesda, Maryland. Data were collected before RT (T1) and one year after RT (T2). Fatigue was assessed using the Functional Assessment of Cancer Therapy-Fatigue questionnaire (FACT-F). Whole genome microarray and cytokine multiplex panel examined fatigue-related transcriptome and serum cytokine changes, respectively. The significantly changed cytokine from the initial investigation was validated using sera from 46 men two years after completing RT (T3) for prostate cancer at Georgetown University Hospital, Washington, DC. Further in vitro validation determined the effect of the significantly changed cytokine on cell viability as quantified by MTT assay. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and TRAIL decoy receptor, TNFRSF10C (TRAIL-R3), were significantly upregulated in fatigued subjects (n=15) at T2. Cognitive deficits were also observed in fatigued subjects at T2. Further, TRAIL correlated with fatigue at T3 in a separate cohort. TRAIL caused selective cytotoxicity in neuronal cells, but not in microglial and muscle cells, in vitro. Late-onset inflammation directed by TRAIL may play a role in chronic fatigue pathogenesis in prostate cancer survivors. Selective vulnerability of neurons to TRAIL may contribute to chronic fatigue-related cognitive deficits.