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Tumorsphere Derivation and Treatment from Primary Tumor Cells Isolated from Mouse Rhabdomyosarcomas
Published on: September 13, 2019
Targeting ferroptosis in rhabdomyosarcoma cells
Jasmin Dächert1, Vanessa Ehrenfeld1, Karoline Habermann1
1Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany.
Abstract:
Recent data suggest that rhabdomyosarcoma (RMS) cells might be vulnerable to oxidative stress-induced cell death. Here, we show that RMS are susceptible to cell death induced by Erastin, an inhibitor of the glutamate/cystine antiporter xc- that can increase reactive oxygen species (ROS) production via glutathione (GSH) depletion. Prior to cell death, Erastin caused GSH depletion, ROS production and lipid peroxidation. Importantly, pharmacological inhibitors of lipid peroxidation (i.e., Ferrostatin-1, Liproxstatin-1), ROS scavengers (i.e., α-Tocopherol, GSH) and the iron chelator Deferoxamine inhibited ROS accumulation, lipid peroxidation and cell death, consistent with ferroptosis. Interestingly, the broad-spectrum protein kinase C (PKC) inhibitor Bisindolylmaleimide I as well as the PKCα- and β-selective inhibitor Gö6976 significantly reduced Erastin-induced cell death. Similarly, genetic knockdown of PKCα significantly protected RMS cells from Erastin-induced cell death. Furthermore, the broad-spectrum nicotinamide adenine dinucleotide phosphate-oxidase (NOX) inhibitor Diphenyleneiodonium and the selective NOX1/4 isoform inhibitor GKT137831 significantly decreased Erastin-stimulated ROS, lipid ROS and cell death. These data provide new insights into the molecular mechanisms of ferroptosis in RMS, contributing to the development of new redox-based treatment strategies.
Insights
Rhabdomyosarcoma cells undergo oxidative stress-induced death when treated with Erastin, a ferroptosis inducer. Protein Kinase C alpha (PKCα) and NADPH oxidase (NOX) pathways are key regulators of this cell death process.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Rhabdomyosarcoma (RMS) cells may be susceptible to oxidative stress.
- Erastin, a glutamate/cystine antiporter inhibitor, induces cell death by increasing reactive oxygen species (ROS) via glutathione (GSH) depletion.
- Understanding ferroptosis mechanisms in RMS is crucial for developing novel therapies.
Purpose of the Study:
- To investigate the susceptibility of RMS cells to Erastin-induced ferroptosis.
- To elucidate the molecular mechanisms, including the roles of protein kinase C (PKC) and NADPH oxidase (NOX) pathways, in Erastin-induced cell death in RMS.
Main Methods:
- RMS cell lines were treated with Erastin.
- Assessed GSH depletion, ROS production, and lipid peroxidation.
- Utilized pharmacological inhibitors (Ferrostatin-1, Liproxstatin-1, α-Tocopherol, GSH, Deferoxamine, Bisindolylmaleimide I, Gö6976, Diphenyleneiodonium, GKT137831).
- Performed genetic knockdown of PKCα.
Main Results:
- Erastin induced GSH depletion, ROS production, and lipid peroxidation in RMS cells.
- Inhibitors of lipid peroxidation, ROS scavengers, and an iron chelator demonstrated ferroptosis.
- PKC inhibitors (broad-spectrum and PKCα/β-selective) and PKCα knockdown significantly reduced Erastin-induced cell death.
- NOX inhibitors (broad-spectrum and NOX1/4-selective) decreased Erastin-stimulated ROS, lipid ROS, and cell death.
Conclusions:
- RMS cells are sensitive to Erastin-induced ferroptosis.
- PKCα and NOX pathways are critical mediators of ferroptosis in RMS.
- These findings support the development of redox-based therapeutic strategies for rhabdomyosarcoma.
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