mGluR5 mediates post-radiotherapy fatigue development in cancer patients

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.

Cognitive and motor aspects of cancer‐related fatigue

“…Oxidative damage induced by RT can target sarcoplasmic reticulum calcium release channels affecting force generation capacity, as well as caspase/calpain pathways leading to contractile protein catabolism and muscle weakness . In addition to directly influencing motor fatigability in the periphery, inflammatory mediators can cross the blood‐brain barrier resulting in secondary inflammation in the brain and cognitive impairment . In fact, prefrontal cortex dysfunction and executive function impairment have been observed in cancer patients, consistent with our finding that fatigued subjects exhibited higher interference scores, a process that requires executive inhibitory control.…”

Co-Occurring Symptoms Contribute to Persistent Fatigue in Prostate Cancer

“…In our previous study, acute fatigue during RT eventually resolved after treatment in most of the patients, and the acute fatigue experience was related to anemia as a result of a combination of ADT and RT [9]. Persistent fatigue, however, can last up to 1 year after RT and was related to chronic inflammation driven by proinflammatory gene expression downstream of NF-κB transcriptional activation [8, 11]. In fact, the role of inflammation has been implicated in all three of the fatigue-associated symptoms (depression, urinary symptoms, and pain) [39-42].…”

“…In a previous study we demonstrated that acute fatigue (fatigue during RT) was associated with hematologic toxicities that arise from a combination of androgen deprivation therapy (ADT) and RT [9]. Persistent fatigue after RT, on the other hand, is thought to be mediated by inflammation occurring during RT [3, 8, 10, 11]. In addition to inflammation, there is evidence that clinical variables can influence the persistent fatigue experience after RT.…”

The State of the Science in Patient-Reported Outcomes for Patients with Lung Cancer

“…78 Other gene expression studies have been undertaken in cancer populations such as those with breast cancer, 79 head and neck cancer, 80,81 and prostate cancer 82,83 ; most of these studies are on cancerrelated fatigue. 84 A study of breast cancer patients showed that epigenomic changes, such as DNA methylation, was related to inflammation that may be linked to fatigue or depressive symptoms. 85 A small study of oncology patients receiving pelvic radiotherapy explored gut microbiome changes and their association with symptoms.…”