Metabolic Rewiring toward Oxidative Phosphorylation Disrupts Intrinsic Resistance to Ferroptosis of the Colon Adenocarcinoma Cells
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Célia Gotorbe1, Jérôme Durivault1, Willian Meira1
1Medical Biology Department, Centre Scientifique de Monaco (CSM), 98000 Monaco, Monaco.
Abstract:
Glutathione peroxidase 4 (GPX4) has been reported as one of the major targets for ferroptosis induction, due to its pivotal role in lipid hydroperoxide removal. However, recent studies pointed toward alternative antioxidant systems in this context, such as the Coenzyme Q-FSP1 pathway. To investigate how effective these alternative pathways are in different cellular contexts, we used human colon adenocarcinoma (CRC) cells, highly resistant to GPX4 inhibition. Data obtained in the study showed that simultaneous pharmacological inhibition of GPX4 and FSP1 strongly compromised the survival of the CRC cells, which was prevented by the ferroptosis inhibitor, ferrostatin-1. Nonetheless, this could not be phenocopied by genetic deletion of FSP1, suggesting the development of resistance to ferroptosis in FSP1-KO CRC cells. Considering that CRC cells are highly glycolytic, we used CRC Warburg-incompetent cells, to investigate the role metabolism plays in this phenomenon. Indeed, the sensitivity to inhibition of both anti-ferroptotic axes (GPx4 and FSP1) was fully revealed in these cells, showing typical features of ferroptosis. Collectively, data indicate that two independent anti-ferroptotic pathways (GPX4-GSH and CoQ10-FSP1) operate within the overall physiological context of cancer cells and in some instances, their inhibition should be coupled with other metabolic modulators, such as inhibitors of glycolysis/Warburg effect.
Insights
Two antioxidant pathways, Glutathione peroxidase 4 (GPX4) and Coenzyme Q-FSP1, protect cancer cells from ferroptosis. Inhibiting both, especially in glycolytic cells, effectively induces cell death.
Area of Science:
- Biochemistry
- Cell Biology
- Cancer Research
Background:
- Glutathione peroxidase 4 (GPX4) is a key enzyme in removing lipid hydroperoxides and a target for ferroptosis induction.
- Alternative antioxidant systems, like the Coenzyme Q-FSP1 pathway, also play a role in ferroptosis regulation.
- Human colon adenocarcinoma (CRC) cells exhibit resistance to GPX4 inhibition, necessitating investigation into alternative pathways.
Purpose of the Study:
- To investigate the effectiveness of alternative antioxidant pathways in different cellular contexts, specifically in CRC cells.
- To explore the interplay between GPX4, FSP1, and cellular metabolism in ferroptosis resistance.
- To determine if combined inhibition of GPX4 and FSP1 can overcome resistance and induce ferroptosis.
Main Methods:
- Utilized human colon adenocarcinoma (CRC) cells, including Warburg-incompetent variants.
- Employed pharmacological inhibition of GPX4 and FSP1.
- Used genetic deletion of FSP1 (FSP1-KO) to assess its role.
- Administered the ferroptosis inhibitor ferrostatin-1 for control experiments.
Main Results:
- Simultaneous pharmacological inhibition of GPX4 and FSP1 significantly reduced CRC cell survival, an effect reversed by ferrostatin-1.
- Genetic deletion of FSP1 did not replicate the sensitivity seen with pharmacological inhibition, suggesting acquired resistance.
- Warburg-incompetent CRC cells showed heightened sensitivity to combined GPX4 and FSP1 inhibition, exhibiting clear ferroptosis features.
- Metabolism, particularly glycolysis, influences sensitivity to ferroptosis induction.
Conclusions:
- Two independent anti-ferroptotic pathways, GPX4-GSH and CoQ10-FSP1, are crucial in cancer cells.
- Combined inhibition of GPX4 and FSP1 can be a viable strategy to induce ferroptosis.
- Targeting glycolysis or the Warburg effect alongside these pathways may enhance therapeutic efficacy against resistant cancers.
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