Research ArticlePain

Decreased abundance of TRESK two-pore domain potassium channels in sensory neurons underlies the pain associated with bone metastasis

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Sci. Signal.  16 Oct 2018:
Vol. 11, Issue 552, eaao5150
DOI: 10.1126/scisignal.aao5150

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VEGF, channels, and metastatic pain

Metastatic cancer in the bone is painful. Yang et al. found that the growth factor VEGF, which is well known for its role in tumor-supportive angiogenesis, directly contributes to this pain. Cell cultures and tissue from a rat model of bone metastatic breast cancer revealed that tumor-secreted VEGF activated a negative-feedback pathway through which the expression of the potassium channel TRESK was repressed. Loss of potassium current through TRESK increased the excitability of sensory neurons and made the animals hypersensitive to heat and touch near the bone lesion. Blocking this pathway restored channel activity and alleviated pain in the animals.

Abstract

Cancer-associated pain is debilitating. Understanding the mechanisms that cause it can inform drug development that may improve quality of life in patients. Here, we found that the reduced abundance of potassium channels called TRESK in dorsal root ganglion (DRG) neurons sensitized nociceptive sensory neurons and cancer-associated pain. Overexpressing TRESK in DRG neurons suppressed tumor-induced neuronal hyperexcitability and pain hypersensitivity in bone metastasis model rats, whereas knocking down TRESK increased neuronal hyperexcitability and pain hypersensitivity in normal rats. Mechanistically, tumor-associated production of vascular endothelial growth factor (VEGF) activated the receptor VEGFR2 on DRGs, which increased the abundance of the calcineurin inhibitor DSCR1, which, in turn, decreased calcineurin-mediated activation of the transcription factor NFAT, thereby reducing the transcription of the gene encoding TRESK. Intrathecal application of exogenous calcineurin to tumor-bearing rats rescued TRESK abundance and abrogated both DRG hyperexcitability and pain hypersensitivity, whereas either inhibition or knockdown of calcineurin in normal rats reduced TRESK abundance and increased DRG excitability and pain sensitivity. These findings identify a potentially targetable mechanism that may cause bone metastasis–associated pain in cancer patients.

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