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Blockers of Wnt3a, Wnt10a, or beta-Catenin Prevent Chemotherapy-Induced Neuropathic Pain In Vivo

Title
Blockers of Wnt3a, Wnt10a, or beta-Catenin Prevent Chemotherapy-Induced Neuropathic Pain In Vivo
Author(s)
Kim, Hee KeeBae, JingiLee, Sung HoHwang, Seon-HeeKim, Min-SikKim, Moon JongJun, SoheeCervantes, Chris L.Jung, Youn-SangBack, SeunghoonLee, HangyeoreLee, Seung-EunDougherty, Patrick M.Lee, Sang-WonPark, Jae-IlAbdi, Salahadin
Issued Date
2021-01
Citation
Neurotherapeutics, v.18, no.1, pp.601 - 614
Type
Article
Author Keywords
Chemotherapy-induced neuropathic painWnt ligandWnt3aWnt10abeta-cateninprevention
Keywords
MMUNOREACTIVE NERVE-FIBERSWNT/BETA-CATENINSPINAL-CORDPEPTIDE CGRPPERIPHERAL-NERVEPACLITAXELSYSTEMRATINHIBITIONACTIVATIONbz
ISSN
1933-7213
Abstract
Although chemotherapy is a key cancer treatment, many chemotherapeutic drugs produce chronic neuropathic pain, called chemotherapy-induced neuropathic pain (CINP), which is a dose-limiting adverse effect. To date, there is no medicine that prevents CINP in cancer patients and survivors. We determined whether blockers of the canonical Wnt signaling pathway prevent CINP. Neuropathic pain was induced by intraperitoneal injection of paclitaxel (PAC) on four alternate days in male Sprague-Dawley rats or male Axin2-LacZ knock-in mice. XAV-939, LGK-974, and iCRT14, Wnt/β-catenin blockers, were administered intraperitoneally as a single or multiple doses before or after injury. Mechanical allodynia, phosphoproteome profiling, Wnt ligands, and inflammatory mediators were measured by von Frey filament, phosphoproteomics, reverse transcription-polymerase chain reaction, and Western blot analysis. Localization of β-catenin was determined by immunohistochemical analysis in the dorsal root ganglia (DRGs) in rats and human. Our phosphoproteome profiling of CINP rats revealed significant phosphorylation changes in Wnt signaling components. Importantly, repeated systemic injections of XAV-939 or LGK-974 prevented the development of CINP in rats. In addition, XAV-939, LGK-974, and iCRT14 ameliorated CINP. PAC increased Wnt3a and Wnt10a, activated β-catenin in DRG, and increased monocyte chemoattractant protein-1 and interleukin-1β in DRG. PAC also upregulated rAxin2 in mice. Furthermore, β-catenin was expressed in neurons, including calcitonin gene–related protein-expressing neurons and satellite cells in rat and human DRG. In conclusion, chemotherapy increases Wnt3a, Wnt10a, and β-catenin in DRG and their pharmacological blockers prevent and ameliorate CINP, suggesting a target for the prevention and treatment of CINP. © 2020, The American Society for Experimental NeuroTherapeutics, Inc.
URI
http://hdl.handle.net/20.500.11750/12935
DOI
10.1007/s13311-020-00956-w
Publisher
Springer Science and Business Media Deutschland GmbH
Related Researcher
  • 김민식 Kim, Min-Sik
  • Research Interests Mass Spectrometry; Proteomics; Cancer Proteogenomics; Biomarker Discovery; Integrative Multi-Omics; LC-MS
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Department of New Biology Laboratory for QBIO and Precision Medicine 1. Journal Articles

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