The role of TRAIL in fatigue induced by repeated stress from radiotherapy.
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 role of chronic inflammation in fatigue following repeated stress from radiotherapy. Fatigue and non-fatigue categories were assessed using ≥ 3-point change in Functional Assessment of Cancer Therapy-Fatigue questionnaire (FACT-F) administered to participants at baseline/before radiotherapy and one year post-radiotherapy. Whole genome microarray and cytokine multiplex panel were used to examine fatigue-related transcriptome and serum cytokine changes, respectively. The study included 86 subjects (discovery phase n = 40, validation phase n = 46). The sample in the discovery phase included men with prostate cancer scheduled to receive external-beam radiotherapy. A panel of 48 cytokines were measured and the significantly changed cytokine found in the discovery phase was validated using sera from a separate cohort of men two years after completing radiotherapy for prostate cancer at a different institution. Effects of the significantly changed cytokine on cell viability was quantified using the MTT assay. During the discovery phase, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and TRAIL decoy receptor, TNFRSF10C (TRAIL-R3), were significantly upregulated in fatigued (≥3-point decrease from baseline to 1yr-post radiotherapy) subjects (n = 15). In the validation phase, TRAIL correlated with fatigue scores 2yrs post-radiotherapy. 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 fatigue pathogenesis post-repeated stress from irradiation.
National Institute of Nursing Research, National Institutes of Health, Bethesda, MD, USA. Electronic address: rebekah.feng@nih.gov.
Li Rebekah
LR
Feng
Department of Radiation Medicine, Georgetown University Hospital, Washington, DC, USA. Electronic address: Simeng.Suy@gunet.georgetown.edu.
Simeng
S
Suy
Department of Radiation Medicine, Georgetown University Hospital, Washington, DC, USA. Electronic address: spc9@gunet.georgetown.edu.
Sean P
SP
Collins
National Institute of Nursing Research, National Institutes of Health, Bethesda, MD, USA. Electronic address: saliganl@mail.nih.gov.
Leorey N
LN
Saligan
D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D045744:Cell Line, Tumor; D016207:Cytokines / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005221:Fatigue / Q000209:etiology*; D005260:Female; D006801:Humans; D008297:Male; D046228:Microarray Analysis; D009369:Neoplasms / Q000532:radiotherapy; D009447:Neuroblastoma / Q000473:pathology; D011569:Psychiatric Status Rating Scales; D011878:Radiotherapy / Q000009:adverse effects*; D015203:Reproducibility of Results; D013315:Stress, Psychological / Q000150:complications* / Q000209:etiology*; D011795:Surveys and Questionnaires; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055815:Young Adult
D016207:Cytokines; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha