Ferroptosis: Cancer Stem Cells Rely on Iron until “to Die for” It

Cosialls, Emma; Hage, Rawad El; Santos, Leïla Dos; Gong, Chang; Mehrpour, Maryam; Hamaï, Ahmed

doi:10.3390/cells10112981

Cited by 54 publications

(59 citation statements)

References 189 publications

(173 reference statements)

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“…Ferroptosis is an iron-ion-dependent form of non-apoptotic cell death leading to oxidative cell death. Surprisingly, CSCs are accumulating iron [ 76 ] and could be specifically targeted with iron-chelating substances such as salinomycin. In this line, it was shown that salinomycin could induce iron load in lysosomes followed by iron-mediated production of reactive oxygen species leading to cell death [ 77 ].…”

Section: The Transcription Factor Nf-κb As a Target In Cancer Stem Cellsmentioning

confidence: 99%

Targeting NF-κB Signaling in Cancer Stem Cells: A Narrative Review

et al. 2022

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Among the cell populations existing within a tumor, cancer stem cells are responsible for metastasis formation and chemotherapeutic resistance. In the present review, we focus on the transcription factor NF-κB, which is present in every cell type including cancer stem cells. NF-κB is involved in pro-tumor inflammation by its target gene interleukin 1 (IL1) and can be activated by a feed-forward loop in an IL1-dependent manner. Here, we summarize current strategies targeting NF-κB by chemicals and biologicals within an integrated cancer therapy. Specifically, we start with a tyrosine kinase inhibitor targeting epidermal growth factor (EGF)-receptor-mediated phosphorylation. Furthermore, we summarize current strategies of multiple myeloma treatment involving lenalidomide, bortezomib, and dexamethasone as potential NF-κB inhibitors. Finally, we discuss programmed death-ligand 1 (PD-L1) as an NF-κB target gene and its role in checkpoint therapy. We conclude, that NF-κB inhibition by specific inhibitors of IκB kinase was of no clinical use but inhibition of upstream and downstream targets with drugs or biologicals might be a fruitful way to treat cancer stem cells.

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Section: The Transcription Factor Nf-κb As a Target In Cancer Stem Cellsmentioning

confidence: 99%

Targeting NF-κB Signaling in Cancer Stem Cells: A Narrative Review

et al. 2022

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“…The downside is that the iron dependency at the same time makes cancer cells more vulnerable to ferroptosis, which therefore might be considered as a druggable “Achilles heel”. Several ferroptosis inducers have been so far identified and approved with the expectation to bypass the disadvantages of traditional chemotherapies based on induction of apoptosis ( 44 , 45 ). Numerous studies have shown that ferroptosis has consistent antitumor effects or, alternatively, enhances chemosensitivity in OVCA ( 21 ).…”

Section: Discussionmentioning

confidence: 99%

Iron Administration Overcomes Resistance to Erastin-Mediated Ferroptosis in Ovarian Cancer Cells

et al. 2022

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ObjectivesDeveloping novel therapeutic approaches to defeat chemoresistance is the major goal of ovarian cancer research. Induction of ferroptosis has shown promising antitumor effects in ovarian cancer cells, but the existence of still undefined genetic and metabolic determinants of susceptibility has so far limited the application of ferroptosis inducers in vivo.MethodsErastin and/or the iron compound ferlixit were used to trigger ferroptosis in HEY, COV318, PEO4, and A2780CP ovarian cancer cell lines. Cell viability and cell death were measured by MTT and PI flow cytometry assay, respectively. The “ballooning” phenotype was tested as ferroptosis specific morphological feature. Mitochondrial dysfunction was evaluated based on ultrastructural changes, mitochondrial ROS, and mitochondrial membrane polarization. Lipid peroxidation was tested through both C11-BODIPY and malondialdehyde assays. VDAC2 and GPX4 protein levels were quantified as additional putative indicators of mitochondrial dysfunction or lipid peroxidation, respectively. The effect of erastin/ferlixit treatments on iron metabolism was analyzed by measuring intracellular labile iron pool and ROS. FtH and NCOA4 were measured as biomarkers of ferritinophagy.ResultsHere, we provide evidence that erastin is unable to induce ferroptosis in a series of ovarian cancer cell lines. In HEY cells, provided with a high intracellular labile iron pool, erastin treatment is accompanied by NCOA4-mediated ferritinophagy and mitochondrial dysfunction, thus triggering ferroptosis. In agreement, iron chelation counteracts erastin-induced ferroptosis in these cells. COV318 cells, with low baseline intracellular labile iron pool, appear resistant to erastin treatment. Notably, the use of ferlixit sensitizes COV318 cells to erastin through a NCOA4-independent intracellular iron accumulation and mitochondrial dysfunction. Ferlixit alone mimics erastin effects and promotes ferroptosis in HEY cells.ConclusionThis study proposes both the baseline and the induced intracellular free iron level as a significant determinant of ferroptosis sensitivity and discusses the potential use of ferlixit in combination with erastin to overcome ferroptosis chemoresistance in ovarian cancer.

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“…Interestingly, recent discoveries indicated that cancer stem cells (CSCs) might be sensitive to ferroptosis due to their relatively strong dependency on the lipid intake pathways and higher intracellular iron levels compared with regular cancer cells ( 132 , 133 ). Therefore, interference with GPX4 pathways seems to sensitize CSCs to ferroptosis ( 134 – 136 ). Furthermore, cytotoxic CD8 + T cells could enhance tumor cell lipid peroxidation caused by ferroptosis, thus achieving higher efficacy of PD1 checkpoint blockade therapy ( 137 ).…”

Section: Ferroptosismentioning

confidence: 99%

Programmed Cell Death Tunes Tumor Immunity

et al. 2022

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The demise of cells in various ways enables the body to clear unwanted cells. Studies over the years revealed distinctive molecular mechanisms and functional consequences of several key cell death pathways. Currently, the most intensively investigated programmed cell death (PCD) includes apoptosis, necroptosis, pyroptosis, ferroptosis, PANoptosis, and autophagy, which has been discovered to play crucial roles in modulating the immunosuppressive tumor microenvironment (TME) and determining clinical outcomes of the cancer therapeutic approaches. PCD can play dual roles, either pro-tumor or anti-tumor, partly depending on the intracellular contents released during the process. PCD also regulates the enrichment of effector or regulatory immune cells, thus participating in fine-tuning the anti-tumor immunity in the TME. In this review, we focused primarily on apoptosis, necroptosis, pyroptosis, ferroptosis, PANoptosis, and autophagy, discussed the released molecular messengers participating in regulating their intricate crosstalk with the immune response in the TME, and explored the immunological consequence of PCD and its implications in future cancer therapy developments.

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Ferroptosis: Cancer Stem Cells Rely on Iron until “to Die for” It

Cited by 54 publications

References 189 publications

Targeting NF-κB Signaling in Cancer Stem Cells: A Narrative Review

Targeting NF-κB Signaling in Cancer Stem Cells: A Narrative Review

Iron Administration Overcomes Resistance to Erastin-Mediated Ferroptosis in Ovarian Cancer Cells

Programmed Cell Death Tunes Tumor Immunity

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