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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\u2009min before irradiation at 8\u2009Gy in a Mark-1 \u03b3-irradiator. NF-\u03baB activation was assessed using a NF-\u03baB\/Jurkat\/GFP Transcriptional Reporter Cell Line. LDA achieved 83.3% accuracy in predicting post-radiotherapy fatigue. \u201cGlutamate receptor signaling\u201d was the most significant (<jats:italic>p<\/jats:italic>\u2009=\u20090.0002) 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-\u03baB 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.<\/jats:p>","DOI":"10.1038\/s41398-018-0161-3","type":"journal-article","created":{"date-parts":[[2018,5,30]],"date-time":"2018-05-30T11:18:53Z","timestamp":1527679133000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["mGluR5 mediates post-radiotherapy fatigue development in cancer patients"],"prefix":"10.1038","volume":"8","author":[{"given":"Li Rebekah","family":"Feng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4758-2832","authenticated-orcid":false,"given":"Juan Luis","family":"Fern\u00e1ndez-Mart\u00ednez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristien J.M.","family":"Zaal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8555-3832","authenticated-orcid":false,"given":"Enrique J","family":"deAndr\u00e9s-Galiana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian S.","family":"Wolff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leorey N.","family":"Saligan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,5,30]]},"reference":[{"key":"161_CR1","doi-asserted-by":"publisher","first-page":"1012","DOI":"10.6004\/jnccn.2015.0122","volume":"13","author":"AM Berger","year":"2015","unstructured":"Berger, A. 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