1 Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, Ontario, Canada.
2 Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Mol Pain. 2018 Jan-Dec;14:1744806918776467. doi: 10.1177/1744806918776467.
Breast cancer cells release the signalling molecule glutamate via the system x 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. We have characterized the effects of the selective TrkA inhibitor AG879 on system x 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 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-mediated cancer pain. System x-mediated TrkA activation therefore presents a promising target for therapeutic intervention in cancer pain treatment.
乳腺癌细胞通过系统 x 反向转运蛋白释放信号分子谷氨酸，该转运蛋白上调以交换细胞外胱氨酸以换取细胞内谷氨酸，从而防止氧化应激。在这里，我们证明这种转运蛋白的功能受神经生长因子对其同源受体酪氨酸激酶 TrkA 的作用的影响，并且抑制该复合物可能通过其对系统 x 的功能亚基 xCT 的下游作用来减轻癌症引起的骨痛。我们已经描述了选择性 TrkA 抑制剂 AG879 对 4T1 鼠和 MDA-MB-231 人乳腺癌细胞中系统 x 活性的影响，以及它对我们经过验证的免疫活性小鼠癌症引起的骨痛模型中痛觉的影响，其中 BALB/c 小鼠股骨内接种 4T1 鼠癌细胞。AG879 降低了功能系统 x 活性，如胱氨酸摄取和谷氨酸释放所测量的，并且抑制了肿瘤-bearing 动物的痛觉和生理相关反应。总之，这些数据表明神经生长因子对 TrkA 的激活可能对系统 x 介导的癌症疼痛具有功能意义。因此，系统 x 介导的 TrkA 激活为癌症疼痛治疗的治疗干预提供了有希望的靶标。
