Metabolic Rewiring toward Oxidative Phosphorylation Disrupts Intrinsic Resistance to Ferroptosis of the Colon Adenocarcinoma Cells

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.

Mechanistic elucidation of ferroptosis and ferritinophagy: implications for advancing our understanding of arthritis

“…This unique phenotype could be ameliorated by ferroptosis inhibitors but remained impervious to interventions involving apoptosis and necroptosis inhibitors. This underscores the potential of FSP1 as a strategic ferroptosis modulator ( Gotorbe et al, 2022 ), with the noteworthy distinction that its inhibitory prowess is GSH-independent ( Doll et al, 2019 ). The FSP1-CoQ10-NAD(P)H pathway operates as an independent and parallel system, collaboratively working with GPX4 and glutathione to inhibit phospholipid peroxidation and ferroptosis.…”

Energy Metabolism as a Therapeutic Target in Cancer: The Role of Coenzyme Q10

“…CoQ10 can also contribute to changes in mitochondrial activity due to a more respiratory phenotype that can negatively affect cell growth. Increasing oxidative phosphorylation in mitochondria produces a metabolic rewiring that disrupts intrinsic resistance to ferroptosis in colon adenocarcinoma cells, indicating that improving oxidative phosphorylation activity can impair cancer progression [82]. Interestingly, CoQ10 supplementation can increase oxidative phosphorylation and reduce the dependence of tumour cells on glycolysis with this mechanism based on cell growth, metastasis, and immune evasion [83].…”

Drug Repurposing‐Based Brain‐Targeting Self‐Assembly Nanoplatform Using Enhanced Ferroptosis against Glioblastoma

“…The cysteine/GSH/GPX4 axis has been reported to be the key axis of ferroptosis. [ 44 ] During ferroptosis, the cellular antioxidant system is activated. GPX4 is an antioxidant molecule, and GSH is a substrate of GPX4 in the cellular antioxidant system, converting toxic phospholipid peroxides into nontoxic phospholipids and oxidizing glutathione to prevent ferroptosis.…”