Hsieh Chia-Jung, Cirrincione Anthony M, Vlach Mikaela R, Diaz Antonio Cadiz, Schmidt Natalie A, Li Xin, Gutierrez Sergio, Ugo Marie J, Amaya Sanchez Maria Celina, Reimonn Cassandra A, Wuchty Stefan, Pellegrini Adriana D, Rude Leah Rk, Pappalardo Leah G, Regan Daniel P, Zhao Bowen, Zhang Fuwu, Howell Caitlin, Hrstka Sybil, Dasari Surendra, Capobianco Enrico, Lisse Thomas S, Harrison Benjamin J, Staff Nathan P, Xu Mike Xiangxi, Rieger Sandra
Department of Biology, University of Miami, Coral Gables, Florida 33146, USA.
Department of Cell Biology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
Res Sq. 2025 Aug 20:rs.3.rs-5470731. doi: 10.21203/rs.3.rs-5470731/v1.
Taxanes are frontline chemotherapeutics that stabilize microtubules, induce mitotic arrest, and drive tumor remission. However, their off-target effects in healthy tissues, most notably cutaneous axon degeneration underlying chemotherapy-induced peripheral neuropathy (CIPN), remain poorly understood. Here, we show that paclitaxel induces microtubule fasciculation in epidermal keratinocytes through the mitotic kinesin Eg5, thereby initiating CIPN. Mechanistically, paclitaxel enhances Eg5-dependent fasciculation of detyrosinated (stabilized) microtubules, which constrict and breach the nuclear lamina. This deformation triggers tension-dependent NADPH oxidase-mediated nuclear ROS (X-ROS) formation upstream of transcription, a pathway we previously demonstrated drives sensory axon degeneration. Employing a cross-species framework spanning zebrafish, mice, human skin biopsies, and a breast adenocarcinoma cell line, we uncover a conserved paclitaxel-Eg5 mechanism leading to fasciculation of stable microtubules in both healthy epidermis and cancer cells. These findings highlight the dualistic nature of paclitaxel action and underscore the challenge of preserving anticancer efficacy while preventing neurotoxic side effects.
紫杉烷类是一线化疗药物，可稳定微管、诱导有丝分裂停滞并促使肿瘤缓解。然而，它们在健康组织中的脱靶效应，尤其是化疗诱导的周围神经病变（CIPN）背后的皮肤轴突变性，仍知之甚少。在此，我们表明紫杉醇通过有丝分裂驱动蛋白Eg5在表皮角质形成细胞中诱导微管束状化，从而引发CIPN。从机制上讲，紫杉醇增强了依赖Eg5的去酪氨酸化（稳定）微管的束状化，这些微管会收缩并破坏核纤层。这种变形触发了转录上游依赖张力的NADPH氧化酶介导的核ROS（X-ROS）形成，我们之前证明该途径会驱动感觉轴突变性。利用跨越斑马鱼、小鼠、人类皮肤活检和乳腺腺癌细胞系的跨物种框架，我们发现了一种保守的紫杉醇-Eg5机制，该机制导致健康表皮和癌细胞中稳定微管的束状化。这些发现突出了紫杉醇作用的二元性，并强调了在预防神经毒性副作用的同时保持抗癌疗效的挑战。
