Journal
ANTIOXIDANTS
Volume 11, Issue 12, Pages -Publisher
MDPI
DOI: 10.3390/antiox11122412
Keywords
ferroptosis; glutathione peroxidase 4; ferroptosis suppressor protein 1; colorectal adenocarcinoma; Warburg effect; OXPHOS
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This study reveals that simultaneous inhibition of GPX4 and FSP1 strongly compromises the survival of colon adenocarcinoma cells, suggesting the presence of resistance to ferroptosis in FSP1-deficient cells. Additionally, inhibition of both anti-ferroptotic pathways shows higher sensitivity in CRC Warburg-incompetent cells, indicating typical features of ferroptosis.
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.
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