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
- Animals
- Antineoplastic Agents/adverse effects*
- Axons/drug effects
- Embryo, Nonmammalian/drug effects
- Epithelium/drug effects*
- Gene Expression
- Humans
- Keratinocytes/drug effects
- Matrix Metalloproteinase 13/genetics
- Matrix Metalloproteinase Inhibitors/pharmacology*
- Paclitaxel/adverse effects*
- Peripheral Nerves/drug effects*
- Skin/cytology
- Skin/drug effects
- Skin/innervation
- Touch Perception/drug effects
- Toxicity Tests
- Zebrafish
- PubMed
- 27035978 Full text @ Proc. Natl. Acad. Sci. USA
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.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping