PUBLICATION

Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish

Authors
Lisse, T.S., Middleton, L.J., Pellegrini, A.D., Martin, P.B., Spaulding, E.L., Lopes, O., Brochu, E.A., Carter, E.V., Waldron, A., Rieger, S.
ID
ZDB-PUB-160402-1
Date
2016
Source
Proceedings of the National Academy of Sciences of the United States of America   113(15): E2189-98 (Journal)
Registered Authors
Rieger, Sandra
Keywords
MMP-13, Taxol, degeneration, epidermis, regeneration
MeSH Terms
  • Animal Fins/cytology
  • Animal Fins/innervation
  • Gene Expression
  • Skin/cytology
  • Skin/drug effects
  • Skin/innervation
  • Keratinocytes/drug effects
  • Touch Perception/drug effects
  • Epithelium/drug effects*
  • Animals
  • Zebrafish
  • Antineoplastic Agents/adverse effects*
  • Matrix Metalloproteinase 13/genetics
  • Toxicity Tests
  • Matrix Metalloproteinase Inhibitors/pharmacology*
  • Humans
  • Paclitaxel/adverse effects*
  • Embryo, Nonmammalian/drug effects
  • Peripheral Nerves/drug effects*
  • Axons/drug effects
(all 20)
PubMed
27035978 Full text @ Proc. Natl. Acad. Sci. USA
Abstract
Paclitaxel is a microtubule-stabilizing chemotherapeutic agent that is widely used in cancer treatment and in a number of curative and palliative regimens. Despite its beneficial effects on cancer, paclitaxel also damages healthy tissues, most prominently the peripheral sensory nervous system. The mechanisms leading to paclitaxel-induced peripheral neuropathy remain elusive, and therapies that prevent or alleviate this condition are not available. We established a zebrafish in vivo model to study the underlying mechanisms and to identify pharmacological agents that may be developed into therapeutics. Both adult and larval zebrafish displayed signs of paclitaxel neurotoxicity, including sensory axon degeneration and the loss of touch response in the distal caudal fin. Intriguingly, studies in zebrafish larvae showed that paclitaxel rapidly promotes epithelial damage and decreased mechanical stress resistance of the skin before induction of axon degeneration. Moreover, injured paclitaxel-treated zebrafish skin and scratch-wounded human keratinocytes (HEK001) display reduced healing capacity. Epithelial damage correlated with rapid accumulation of fluorescein-conjugated paclitaxel in epidermal basal keratinocytes, but not axons, and up-regulation of matrix-metalloproteinase 13 (MMP-13, collagenase 3) in the skin. Pharmacological inhibition of MMP-13, in contrast, largely rescued paclitaxel-induced epithelial damage and neurotoxicity, whereas MMP-13 overexpression in zebrafish embryos rendered the skin vulnerable to injury under mechanical stress conditions. Thus, our studies provide evidence that the epidermis plays a critical role in this condition, and we provide a previously unidentified candidate for therapeutic interventions.
Genes / Markers
Figures
Figure Gallery (14 images) / 2
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
mdi2010TgTransgenic Insertion
    mdi2011TgTransgenic Insertion
      mdi2012TgTransgenic Insertion
        mdi2013TgTransgenic Insertion
          nc1TgTransgenic Insertion
            w2
              		Point Mutation
              zc7TgTransgenic Insertion
                1 - 7 of 7
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                Human Disease / Model
                No data available
                Sequence Targeting Reagents
                No data available
                Fish
                No data available
                Antibodies
                No data available
                Orthology
                No data available
                Engineered Foreign Genes
                Marker Marker Type Name
                DsRedEFGDsRed
                EGFPEFGEGFP
                GAL4EFGGAL4
                GFPEFGGFP
                HyPerEFGHyPer
                TomatoEFGTomato
                1 - 6 of 6
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                Mapping
                No data available
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                Citation
                Lisse, T.S., Middleton, L.J., Pellegrini, A.D., Martin, P.B., Spaulding, E.L., Lopes, O., Brochu, E.A., Carter, E.V., Waldron, A., Rieger, S. (2016) Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish. Proceedings of the National Academy of Sciences of the United States of America. 113(15):E2189-98.