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Paclitaxel neurotoxicity is triggered by epidermal EG5-dependent microtubule fasciculation and X-ROS formation
Sandra Rieger1, Chia-Jung Hsieh1, Cirrincione Anthony1
1Department of Biology, University of Miami, Coral Gables, Florida 33146, USA.
Abstract:
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 mmp13 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.
Insights
Paclitaxel causes nerve damage by disrupting microtubules in skin cells, leading to chemotherapy-induced peripheral neuropathy (CIPN). This mechanism, involving Eg5 kinesin, affects both healthy skin and cancer cells, posing a treatment challenge.
Area of Science:
- Oncology
- Neuroscience
- Cell Biology
Background:
- Taxanes are crucial chemotherapy drugs for cancer treatment.
- Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating side effect.
- The precise mechanisms underlying taxane-induced neurotoxicity are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanisms by which paclitaxel induces peripheral neuropathy.
- To investigate the role of microtubule dynamics and specific proteins in taxane neurotoxicity.
- To explore potential therapeutic strategies for mitigating CIPN.
Main Methods:
- Utilized a cross-species approach including zebrafish, mice, human skin biopsies, and cell lines.
- Investigated the interaction between paclitaxel, Eg5 kinesin, and microtubule stability.
- Analyzed nuclear lamina integrity, reactive oxygen species (ROS) production, and gene expression (mmp13).
Main Results:
- Paclitaxel induces microtubule fasciculation in epidermal keratinocytes via Eg5 kinesin.
- This process deforms the nuclear lamina, leading to nuclear ROS (X-ROS) formation.
- A conserved paclitaxel-Eg5-microtubule mechanism was identified in both healthy epidermis and cancer cells.
Conclusions:
- Paclitaxel's neurotoxic effects stem from Eg5-mediated microtubule stabilization in keratinocytes, initiating CIPN.
- The findings reveal a dual role of paclitaxel, impacting both cancer cells and healthy tissues.
- Addressing this mechanism is critical for balancing anticancer efficacy and neurotoxic side effects.
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