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Epidermal Eg5 promotes X-ROS dependent paclitaxel neurotoxicity

Diaz, A. C.; Cirrincione, A. M.; Schmidt, N. A.; Ugo, M. J.; Sanchez, M. C. A.; Reimonn, C. A.; Wuchty, S.; Pellegrini, A. D.; Rude, L. R.; Pappalardo, L. G.; Regan, D. P.; Howell, C.; Hrstka, S.; Dasari, S.; Lisse, T. S.; Harrison, B. J.; Xu, M. X.; Staff, N. P.; Rieger, S.

2023-05-23 cell biology
10.1101/2023.05.22.541784 bioRxiv
Show abstract

Taxanes are chemotherapeutic agents that induce microtubule modifications in cancer cells, resulting in cell cycle modifications and tumor remission. Here we show that paclitaxel, a widely used taxane, also induces microtubule modifications in healthy epidermal keratinocytes leading to chemotherapy-induced peripheral neuropathy (CIPN). Paclitaxel activates the cell cycle regulator, Kinesin-5 (Eg5), which promotes microtubule detyrosination and fasciculation (dfMT). Eg5 loss protects neurons from paclitaxel neurotoxicity, whereas keratinocyte-specific overexpression promotes axon degeneration. In vivo imaging and 3D reconstructions of dfMTs and nuclei, combined with mechanotransduction studies further show that dfMTs constrict keratinocyte nuclei, leading to nuclear Nox-dependent reactive oxygen species (X-ROS) formation upstream of MMP-13 and cutaneous sensory axon degeneration. This new insight facilitates our understanding of chemotherapy side effects and highlights the need for targeted therapies.

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