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

Molecular Pain
Tanya MiladinovicGurmit Singh

Abstract

Breast cancer cells release the signalling molecule glutamate via the system xC- 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 xC-. We have characterized the effects of the selective TrkA inhibitor AG879 on system xC- 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 xC- 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 xC--mediated cancer pain. System xC--mediated TrkA...Continue Reading

References

Mar 1, 1992·Arthritis and Rheumatism·L AloeR Levi-Montalcini
Jan 1, 1994·Progress in Brain Research·D W Choi
Jun 27, 1998·The Journal of Biological Chemistry·S DescampsH Hondermarck
Nov 24, 1999·Annals of Surgery·H FriessM W Büchler
Dec 14, 1999·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·N M PeetT M Skerry
Feb 1, 2000·Biochemical and Biophysical Research Communications·C ItzsteinC Chenu
Mar 26, 2003·Brain Research. Molecular Brain Research·Sara TaylorRouel S Roque
Apr 5, 2003·Annual Review of Biochemistry·Eric J Huang, Louis F Reichardt
May 16, 2003·Nature·William J BoyleDavid L Lacey
Aug 29, 2003·Oncogene·Laurent DolléHubert Hondermarck
Jun 15, 2004·Nature Medicine·Makoto InoueHiroshi Ueda
Jul 27, 2005·Pain·Hideaki AsaiYasuo Sugiura
Oct 13, 2006·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Andy Y ShihTimothy H Murphy
Dec 21, 2006·Cancer Metastasis Reviews·William C Dougall, Michelle Chaisson
Apr 24, 2008·Journal of Pharmacological Sciences·Takeshi Takarada, Yukio Yoneda
Jun 16, 2009·Clinical & Experimental Metastasis·Eric P SeidlitzGurmit Singh
Nov 10, 2009·Biochemical and Biophysical Research Communications·Mohit K SharmaGurmit Singh
May 19, 2010·Cancer Treatment Reviews·Robert E ColemanLarry J Suva
Oct 6, 2010·Canadian Journal of Physiology and Pharmacology·Eric P SeidlitzGurmit Singh
Nov 5, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Juan M Jimenez-AndradePatrick W Mantyh
Apr 19, 2011·The Journal of Pain : Official Journal of the American Pain Society·Aaron P BloomPatrick W Mantyh
May 24, 2011·Anesthesiology·Patrick W MantyhDavid L Shelton
Oct 5, 2011·Neuropharmacology·Xiaoqian LiuDoug Lobner
May 12, 2012·Journal of Pharmacological and Toxicological Methods·Ramakrishna NirogiRenny Abraham
Oct 1, 2013·Neuroscience Letters·A N Lozano-OndouaT W Vanderah
Apr 22, 2015·Molecular and Cellular Biochemistry·Katja Linher-MelvilleGurmit Singh

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Citations

Feb 26, 2019·Molecular Pain·Robert G UngardGurmit Singh
Feb 28, 2020·Canadian Journal of Pain = Revue Canadienne De La Douleur·Robert G UngardGurmit Singh

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Methods Mentioned

BETA
transgenic
protein
electrophoresis
protein assay

Software Mentioned

ImageJ
GraphPad QuickCals
GraphPad Prism
DWB

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