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Query: UMLS:C0596240 (
cancer pain
)
3,066
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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.
...
PMID:Functional effects of TrkA inhibition on system x
C
-
-mediated glutamate release and cancer-induced bone pain. 2976 34
Cancers in the bone produce a number of severe symptoms including pain that compromises patient functional status, quality of life, and survival. The source of this pain is multifaceted and includes factors secreted from tumor cells. Malignant cells release the neurotransmitter and cell-signaling molecule glutamate via the oxidative stress-related cystine/glutamate antiporter, system x
C
-
, which reciprocally imports cystine for synthesis of glutathione and the cystine/cysteine redox cycle. Pharmacological inhibition of system x
C
-
has shown success in reducing and delaying the onset of
cancer pain
-related behavior in mouse models. This investigation describes the development of a stable siRNA-induced knockdown of the functional trans-membrane system x
C
-
subunit
xCT
( SLC7A11) in the human breast cancer cell line MDA-MB-231. Clones were verified for
xCT
knockdown at the transcript, protein, and functional levels. RNAseq was performed on a representative clone to comprehensively examine the transcriptional cellular signature in response to
xCT
knockdown, identifying multiple differentially regulated factors relevant to
cancer pain
including nerve growth factor, interleukin-1, and colony-stimulating factor-1. Mice were inoculated intrafemorally and recordings of pain-related behaviors including weight bearing, mechanical withdrawal, and limb use were performed. Animals implanted with
xCT
knockdown cancer cells displayed a delay until the onset of nociceptive behaviors relative to control cells. These results add to the body of evidence suggesting that a reduction in glutamate release from cancers in bone by inhibition of the system x
C
-
transporter may decrease the severe and intractable pain associated with bone metastases.
...
PMID:xCT knockdown in human breast cancer cells delays onset of cancer-induced bone pain. 3079 86
