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

Thomas S. Lissea, Leah J. Middletona, Adriana D. Pellegrinia, Paige B. Martina, Emily L. Spauldinga, Olivia Lopesa, Elizabeth A. Brochua, Erin V. Cartera, Ashley Waldrona, Sandra Riegera

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

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 paclitaxelinduced 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 upregulation 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.

Original languageEnglish (US)
Pages (from-to)E2189-E2198
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number15
DOIs
StatePublished - Apr 12 2016
Externally publishedYes

Keywords

  • Degeneration
  • Epidermis
  • MMP-13
  • Regeneration
  • Taxol

ASJC Scopus subject areas

  • General

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