| Autor: |
Antonio Cadiz Diaz, Anthony M Cirrincione, Natalie A Schmidt, Marie J Ugo, Maria Celina Amaya Sanchez, Cassandra A. Reimonn, Stefan Wuchty, Adriana D Pellegrini, Leah RK Rude, Leah G Pappalardo, Daniel P Regan, Caitlin Howell, Sybil Hrstka, Surendra Dasari, Thomas S Lisse, Benjamin J Harrison, Mike Xiangxi Xu, Nathan P Staff, Sandra Rieger |
| Rok vydání: |
2023 |
| DOI: |
10.1101/2023.05.22.541784 |
| Popis: |
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 vivoimaging 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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