PKCα Inhibition as a Strategy to Sensitize Neuroblastoma Stem Cells to Etoposide by Stimulating Ferroptosis

Abstract

Cancer stem cells (CSCs) are a limited cell population inside a tumor bulk characterized by high levels of glutathione (GSH), the most important antioxidant thiol of which cysteine is the limiting amino acid for GSH biosynthesis. In fact, CSCs over-express xCT, a cystine transporter stabilized on cell membrane through interaction with CD44, a stemness marker whose expression is modulated by protein kinase Cα (PKCα). Since many chemotherapeutic drugs, such as Etoposide, exert their cytotoxic action by increasing reactive oxygen species (ROS) production, the presence of high antioxidant defenses confers to CSCs a crucial role in chemoresistance. In this study, Etoposide-sensitive and -resistant neuroblastoma CSCs were chronically treated with Etoposide, given alone or in combination with Sulfasalazine (SSZ) or with an inhibitor of PKCα (C2-4), which target xCT directly or indirectly, respectively. Both combined approaches are able to sensitize CSCs to Etoposide by decreasing intracellular GSH levels, inducing a metabolic switch from OXPHOS to aerobic glycolysis, down-regulating glutathione-peroxidase-4 activity and stimulating lipid peroxidation, thus leading to ferroptosis. Our results suggest, for the first time, that PKCα inhibition inducing ferroptosis might be a useful strategy with which to fight CSC chemoresistance.

TRPM7 channel inhibition attenuates rheumatoid arthritis articular chondrocyte ferroptosis by suppression of the PKCα-NOX4 axis

“…Recent studies have demonstrated the calcium-activated Protein kinase C α (PKCα) signaling pathway to be involved in RA and ferroptosis [ 28 , 29 ]. Interestingly, RNA-sequencing results also revealed the PKC pathway triggered by erastin was regulated by 2-APB, which demonstrated that PKC may be associated with TRPM7-mediated chondrocyte ferroptosis ( Fig.…”

Antimicrobial Peptides and Cationic Nanoparticles: A Broad-Spectrum Weapon to Fight Multi-Drug Resistance Not Only in Bacteria

“…In fact, after an initial positive response of the anticancer therapy, the onset of MDR and the negative prognosis occurs [ 65 , 66 ]. Cancer cells have been found to acquire an MDR phenotype through several mechanisms, including increased expression of MDR transporters, which increase drug efflux and/or reduce its uptake; defects in the apoptotic program; promotion of the autophagy process; alteration of drug metabolism and cancer cell metabolism and alteration of intracellular redox homeostasis [ 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 ]. Notably, many of these mechanisms are the same as those that allow bacteria to develop antibiotic resistance.…”

In Vitro Assessment of the Role of p53 on Chemotherapy Treatments in Neuroblastoma Cell Lines

“…For this reason, in this work we tried to analyze whether drug resistance in neuroblastoma cell lines is associated with a lack of p53 function and/or with TP53 mutations. Topoisomerase inhibitors (etoposide [30] and doxorubicin [31]) and DNA alkylating substances (cisplatin [32] and melphalan [33]) are chemotherapeutic agents currently administered to neuroblastoma patients. We used these drugs in our study, which we have performed with tolerable doses in vivo [4].…”