Paclitaxel-induced peripheral neuropathy is caused by epidermal ROS and mitochondrial damage through conserved MMP-13 activation

Anthony M Cirrincione,Sandra Rieger,Jacqueline Sagen,Adriana D Pellegrini,Irina Utkina-Sosunova,Marisa E Benjamin,Stanislava Jergova,Francesco Lotti,Jessica R Dominy

doi:10.1038/s41598-020-60990-8

Abstract

Paclitaxel induces peripheral neuropathy as a side effect of cancer treatment. The underlying causes are unclear, but epidermal, unmyelinated axons have been shown to be the first to degenerate. We previously utilized an in vivo zebrafish model to show that the epidermal matrix-metalloproteinase 13 (MMP-13) induces degeneration of unmyelinated axons, whereas pharmacological inhibition of MMP-13 prevented axon degeneration. However, the precise functions by which MMP-13 is regulated and affects axons remained elusive. In this study, we assessed mitochondrial damage and reactive oxygen species (ROS) formation as possible inducers of MMP-13, and we analyzed MMP-13-dependent damage. We show that the small ROS, H2O2, is increased in basal keratinocytes following treatment with paclitaxel. Cytoplasmic H2O2 appears to derive, at least in part, from mitochondrial damage, leading to upregulation of MMP-13, which in turn underlies increased epidermal extracellular matrix degradation. Intriguingly, also axonal mitochondria show signs of damage, such as fusion/fission defects and vacuolation, but axons do not show increased levels of H2O2. Since MMP-13 inhibition prevents axon degeneration but does not prevent mitochondrial vacuolation, we suggest that vacuolization occurs independently of axonal damage. Finally, we show that MMP-13 dysregulation also underlies paclitaxel-induced peripheral neuropathy in mammals, indicating that epidermal mitochondrial H2O2 and its effectors could be targeted for therapeutic interventions.

Highlights

60–70% of cancer patients treated with paclitaxel develop peripheral neuropathy[1]
A prevalent model for paclitaxel neurotoxicity posits that paclitaxel causes axon degeneration by intra-axonal mitochondrial damage and reactive oxygen species (ROS) formation[9,10,11], which parallels findings in cancer cells where paclitaxel treatment in vitro induces mitochondrial damage and ROS, inducing cancer cell apoptosis[8]. It remains unclear whether the observed mitochondrial damage in axons is a cause of axon degeneration or the consequence of degradation processes induced during axon degeneration (Fig. 1a)
Our data suggests a model by which epidermal mitochondrial damage induces H2O2 production leading to increased matrix-metalloproteinase 13 (MMP-13)-dependent matrix degradation and axon degeneration (Fig. S7)

Summary

Introduction

60–70% of cancer patients treated with paclitaxel develop peripheral neuropathy[1]. MCF-7 breast cancer cells treated with the mtROS inducer, rotenone, showed increased ROS production and mmp[2] expression This effect was dependent upon manganese superoxide dismutase[7]. Since paclitaxel shows strong efficacy in the treatment of carcinomas, an epithelial-derived cancer cell type, this chemotherapeutic agent could induce mitochondrial dysfunction in basal epidermal keratinocytes, leading to MMP-13 upregulation and axon degeneration. We assess this idea and analyze how MMP-13 contributes to the degeneration of unmyelinated sensory axons innervating the epidermis

Methods

Results

Conclusion