Functional effects of TrkA inhibition on system x_C^--mediated glutamate release and cancer-induced bone pain

Breast cancer cells release the signalling molecule glutamate via the system x_C^- 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_C^-. We have characterized the effects of the selective TrkA inhibitor AG879 on system x_C^- 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_C^- 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_C^--mediated cancer pain. System x_C^--mediated TrkA activation therefore presents a promising target for therapeutic intervention in cancer pain treatment.