Abstract
Cancer-related fatigue (CRF) is a common burden in cancer patients and little is known about its underlying mechanism. The primary aim of this study was to identify gene signatures predictive of post-radiotherapy fatigue in prostate cancer patients. We employed Fisher Linear Discriminant Analysis (LDA) to identify predictive genes using whole genome microarray data from 36 men with prostate cancer. Ingenuity Pathway Analysis was used to determine functional networks of the predictive genes. Functional validation was performed using a T lymphocyte cell line, Jurkat E6.1. Cells were pretreated with metabotropic glutamate receptor 5 (mGluR5) agonist (DHPG), antagonist (MPEP), or control (PBS) for 20 min before irradiation at 8 Gy in a Mark-1 γ-irradiator. NF-κB activation was assessed using a NF-κB/Jurkat/GFP Transcriptional Reporter Cell Line. LDA achieved 83.3% accuracy in predicting post-radiotherapy fatigue. “Glutamate receptor signaling” was the most significant (p = 0.0002) pathway among the predictive genes. Functional validation using Jurkat cells revealed clustering of mGluR5 receptors as well as increased regulated on activation, normal T cell expressed and secreted (RANTES) production post irradiation in cells pretreated with DHPG, whereas inhibition of mGluR5 activity with MPEP decreased RANTES concentration after irradiation. DHPG pretreatment amplified irradiation-induced NF-κB activation suggesting a role of mGluR5 in modulating T cell activation after irradiation. These results suggest that mGluR5 signaling in T cells may play a key role in the development of chronic inflammation resulting in fatigue and contribute to individual differences in immune responses to radiation. Moreover, modulating mGluR5 provides a novel therapeutic option to treat CRF.
Highlights
Persistent fatigue is a debilitating condition that affects up to 80% of cancer patients[1]
All participants enrolled in this study were euthymic men, 18 years of age or older, who were diagnosed with non-metastatic prostate cancer with or without prior prostatectomy, and were scheduled to receive external beam radiation therapy (EBRT)
We did not observe any significant differences in clinical characteristics between the two groups for age, body mass index (BMI), Gleason scores, T stage, or Prostate specific antigen (PSA) levels (Table 1)
Summary
Persistent fatigue is a debilitating condition that affects up to 80% of cancer patients[1]. It is not uncommon for fatigue to persist long after cancer treatment, and to negatively impact the quality of life in these patients[1,2]. The underlying mechanisms of persistent fatigue remain elusive, emerging evidence suggests that unresolved inflammation after cancer treatment plays a role in the chronicity of cancer fatigue[3,4,5,6,7]. Radiotherapy is a highly effective standard of care treatment for many types of cancer[8]. Unresolved inflammation triggered by repeated stress has been shown to result in “sickness behavior,” a cluster of symptoms including fatigue, depression, and increased sensitivity to pain[5,12,13]
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