“Epidermal Eg5 promotes X-ROS dependent paclitaxel neurotoxicity”
“Epidermal Eg5 promotes X-ROS dependent paclitaxel neurotoxicity”
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.
Staff Nathan P、Rieger Sandra、Diaz Antonio Cadiz、Schmidt Natalie A、Ugo Marie J、Wuchty Stefan、Rude Leah RK、Pappalardo Leah G、Howell Caitlin、Harrison Benjamin J、Xu Mike Xiangxi、Regan Daniel P、Pellegrini Adriana D、Hrstka Sybil、Dasari Surendra、Lisse Thomas S、Reimonn Cassandra A.、Cirrincione Anthony M、Amaya Sanchez Maria Celina
Department of Neurology, Mayo ClinicDepartment of Biology, University of Miami||Sylvester Comprehensive Cancer Center, University of Miami Miller School of MedicineDepartment of Biology, University of MiamiDepartment of Biology, University of MiamiDepartment of Biology, University of MiamiDepartment of Biology, University of Miami||Department of Computer Science, University of MiamiMDI Biological Laboratory, Kathryn W. Davis Center for Regenerative Biology and MedicineMDI Biological Laboratory, Kathryn W. Davis Center for Regenerative Biology and MedicineDepartment of Chemical and Biomedical Engineering, University of MaineDepartment of Cell Biology, University of Miami Miller School of Medicine||Sylvester Comprehensive Cancer Center, University of Miami Miller School of MedicineDepartment of Chemical and Biomedical Engineering, University of MaineMDI Biological Laboratory, Kathryn W. Davis Center for Regenerative Biology and MedicineDepartment of Neurology, Mayo ClinicDepartment of Neurology, Mayo ClinicDepartment of Biology, University of Miami||Sylvester Comprehensive Cancer Center, University of Miami Miller School of MedicineUniversity of New England, Department of Biomedical SciencesDepartment of Biology, University of MiamiDepartment of Cell Biology, University of Miami Miller School of Medicine
肿瘤学神经病学、精神病学药学
microtubulesdetyrosinationpaclitaxelTaxolneuropathyEg5Kif11Kinesin 5keratinocytesfasciculationnucleus
Staff Nathan P,Rieger Sandra,Diaz Antonio Cadiz,Schmidt Natalie A,Ugo Marie J,Wuchty Stefan,Rude Leah RK,Pappalardo Leah G,Howell Caitlin,Harrison Benjamin J,Xu Mike Xiangxi,Regan Daniel P,Pellegrini Adriana D,Hrstka Sybil,Dasari Surendra,Lisse Thomas S,Reimonn Cassandra A.,Cirrincione Anthony M,Amaya Sanchez Maria Celina.“Epidermal Eg5 promotes X-ROS dependent paclitaxel neurotoxicity”[EB/OL].(2025-03-28)[2025-08-22].https://www.biorxiv.org/content/10.1101/2023.05.22.541784.点此复制
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