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bioRxiv · 10.1101/2023.05.22.541784

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.
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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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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. Epidermal Eg5 promotes X-ROS dependent paclitaxel neurotoxicity. https://doi.org/10.1101/2023.05.22.541784

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