Microtubule depolymerization induces ferroptosis in neuroblastoma cells

Area of Science:

• Oncology
• Cell Biology
• Biochemistry

Background:

• Estramustine (EM) is a successful anti-prostate cancer drug with anti-proliferative and cell-death-inducing properties.
• Cancer cells exhibit altered iron metabolism.
• Microtubule disruption is a known effect of EM.

Purpose of the Study:

• To investigate the relationship between microtubule depolymerization and ferroptosis induction by EM in human neuroblastoma cells.
• To explore the role of iron metabolism and oxidative stress in EM-induced cell death.

Main Methods:

• Human neuroblastoma cell lines (SH-SY5Y and IMR-32) were treated with Estramustine.
• Levels of glutathione (GSH), reactive oxygen species (ROS), labile iron pool (LIP), glutathione peroxidase 4 (GPX4), and lipid peroxidation were measured.
• ROS scavengers and ferroptosis inhibitors were used to validate the mechanism.

Main Results:

• EM reduced GSH levels and increased ROS generation, which were mitigated by ROS scavengers.
• EM treatment led to increased LIP, depleted GPX4, and elevated lipid peroxidation, indicating ferroptosis.
• Ferroptosis inhibitors abrogated EM's cytotoxic effects.
• Other microtubule-depolymerizing agents (vinblastine, nocodazole) also increased LIP and lipid peroxidation.

Conclusions:

• Microtubule integrity is coupled to ferroptosis induction.
• Estramustine induces ferroptosis in neuroblastoma cells via microtubule depolymerization and iron dysregulation.
• Microtubule-depolymerizing agents show potential as pro-ferroptosis chemotherapeutics for cancer treatment.