{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T21:18:46Z","timestamp":1793395126591,"version":"4.5.0"},"reference-count":63,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2018,1,1]],"date-time":"2018-01-01T00:00:00Z","timestamp":1514764800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["10810262"],"award-info":[{"award-number":["10810262"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Mol Pain"],"published-print":{"date-parts":[[2018,1]]},"abstract":"<jats:p>\n                    Breast cancer cells release the signalling molecule glutamate via the system x\n                    <jats:sub>C<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    antiporter, which is upregulated to exchange extracellular cystine for intracellular glutamate to protect against oxidative stress. Here, we demonstrate that this antiporter is functionally influenced by the actions of the neurotrophin nerve growth factor on its cognate receptor tyrosine kinase, TrkA, and that inhibiting this complex may reduce cancer-induced bone pain via its downstream actions on xCT, the functional subunit of system x\n                    <jats:sub>C<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    . We have characterized the effects of the selective TrkA inhibitor AG879 on system x\n                    <jats:sub>C<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    activity in murine 4T1 and human MDA-MB-231 mammary carcinoma cells, as well as its effects on nociception in our validated immunocompetent mouse model of cancer-induced bone pain, in which BALB\/c mice are intrafemorally inoculated with 4T1 murine carcinoma cells. AG879 decreased functional system x\n                    <jats:sub>C<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    activity, as measured by cystine uptake and glutamate release, and inhibited nociceptive and physiologically relevant responses in tumour-bearing animals. Cumulatively, these data suggest that the activation of TrkA by nerve growth factor may have functional implications on system x\n                    <jats:sub>C<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    -mediated cancer pain. System x\n                    <jats:sub>C<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    -mediated TrkA activation therefore presents a promising target for therapeutic intervention in cancer pain treatment.\n                  <\/jats:p>","DOI":"10.1177\/1744806918776467","type":"journal-article","created":{"date-parts":[[2018,5,15]],"date-time":"2018-05-15T08:11:31Z","timestamp":1526371891000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":15,"title":["Functional effects of TrkA inhibition on system x\n                    <sub>C<\/sub>\n                    <sup>\u2212<\/sup>\n                    -mediated glutamate release and cancer-induced bone pain"],"prefix":"10.1177","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4129-7950","authenticated-orcid":false,"given":"Tanya","family":"Miladinovic","sequence":"first","affiliation":[{"name":"Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, Ontario, Canada"},{"name":"Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert G","family":"Ungard","sequence":"additional","affiliation":[{"name":"Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, Ontario, Canada"},{"name":"Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Linher-Melville","sequence":"additional","affiliation":[{"name":"Michael G. 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