Role of PKC-α in the induction of ferroptosis: a therapeutic target to fight chemoresistance of cancer stem cells

Cancer stem cells (CSCs) are a small cancer cells population inside the tumor bulk which play a crucial role in tumor recurrence, metastatic dissemination and therapy resistance. CSCs are characterized by high antioxidant defences, such as glutathione (GSH), which by maintaining low production of reactive oxygen species (ROS) confers to CSCs the ability to counteract therapy-induced ROS production favoring the acquisition of resistance. Moreover, GSH is the co‐factor of glutathione peroxidase 4 (GPX4), an enzyme able to reduce phospholipid hydroperoxides into corresponding phospholipid alcohols. In this regard, it has been demonstrated that phospholipid peroxidation together with GPX4 inactivation and GSH depletion led to ferroptosis, an iron-dependent non-apoptotc cell death. CSCs overexpressed xCT, a glutamate-cystine antiport that modulating cysteine availability could limit GSH synthesis. xCT is stabilized at the plasma membrane by CD44, a stem cell marker whose expression is regulated by protein kinase Cα (PKCα). A lot of chemoterapeutics, such as Etoposide, act by increasing ROS levels to eradicate tumor cells. The aim of this study is to modulate GSH levels in order to sensitize CSCs to pro-oxidant effects induced by Etoposide. Therefore, CSCs were selected from HTLA-230, a human neuroblastoma cell line, and from etoposide–resistant cells (ER-CSCs), and then they were treated with Etoposide alone or in combination with sulfasalazine (SSZ), an xCT inhibitor, or with C2-4, a PKC-α inhibitor.