Contribution of Lipid Oxidation and Ferroptosis to Radiotherapy Efficacy

Pearson, Ashley N.; Carmicheal, Joseph; Jiang, Long; Lei, Yu; Green, Michael D.

doi:10.3390/ijms222212603

Cited by 18 publications

(10 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, ferroptosis levels were higher in response/sensitive tumor cases/cells under chemotherapy or radiotherapy treatment (Figures 6D-F). These findings are consistent with the studies in CESC that silencing components of ferroptosis signaling leads to radiotherapy resistance (40,41). A prior study also showed that the chemosensitizing effects of Andrographis were mediated by activation of ferroptosis (42).…”

Section: Discussionsupporting

confidence: 91%

Ferroptosis-Associated Molecular Features to Aid Patient Clinical Prognosis and Therapy Across Human Cancers

et al. 2022

View full text Add to dashboard Cite

Ferroptosis is a new non-apoptotic form that regulates cell death and is mainly dependent on iron-mediated oxidative damage and subsequent cell membrane damage. Ferroptosis may be a potential therapeutic strategy for immunotherapy, chemotherapy, and radiotherapy in human cancers. Numerous studies have analyzed ferroptosis-correlated signatures or genes, but a systematic landscape of associations among tumor ferroptosis, clinical outcomes, tumor microenvironment, and therapies in human cancers is lacking. Here, we developed a relative ferroptosis level (RFL) combined with drive/suppress regulators and validated it in the Gene Expression Omnibus datasets of ferroptotic drug treatment. Based on this effective evaluation method, we classified about 7,000 tumor samples into high and low RFL groups in each cancer type and observed that high RFL cases demonstrate favorable survival outcomes in nine cancer types from The Cancer Genome Atlas. Then, several RFL-correlated candidate genes that have not been reported to be ferroptosis-related were selected and experimentally validated in five cancer cell lines using Erastin treatment. We further showed that both immunostimulatory and immunosuppressive phenotypes were observed in high RFL tumors, suggesting that the consideration of ferroptosis could be a potential strategy in cancer immunotherapy. Moreover, we found that high RFL cases/cells showed responder or sensitivity to chemotherapy and radiotherapy. Our study provides a comprehensive molecular-level understanding of ferroptosis and may have practical implications for clinical cancer therapies, including immunotherapy, chemotherapy, and radiotherapy.

show abstract

Section: Discussionsupporting

confidence: 91%

Ferroptosis-Associated Molecular Features to Aid Patient Clinical Prognosis and Therapy Across Human Cancers

et al. 2022

View full text Add to dashboard Cite

show abstract

“…The analyses reveal a notable increase in lipid peroxidation for the cell lines treated with RT alone. These results were expected, as lipid peroxidation induced by RT has been reported [ 41 ]. Interestingly, however, the levels of lipid peroxidation induced by NBTXR3 + RT is significantly higher in most cell lines tested, compared to RT alone.…”

Section: Resultssupporting

confidence: 84%

Radiotherapy-activated NBTXR3 nanoparticles promote ferroptosis through induction of lysosomal membrane permeabilization

Da Silva,

Bienassis,

Schmitt

et al. 2024

J Exp Clin Cancer Res

View full text Add to dashboard Cite

Purpose Radiotherapy-activated NBTXR3 (NBTXR3 + RT) has demonstrated superior efficacy in cancer cell destruction and tumor growth control, compared to radiotherapy (RT), in preclinical and clinical settings. Previous studies highlighted the immunomodulatory properties of NBTXR3 + RT, such as modification of tumor cell immunogenicity/adjuvanticity, producing an effective local tumor control and abscopal effect, related to an enhanced antitumor immune response. Furthermore, NBTXR3 + RT has shown potential in restoring anti-PD1 efficacy in a refractory tumor model. However, the early events leading to these results, such as NBTXR3 endocytosis, intracellular trafficking and primary biological responses induced by NBTXR3 + RT remain poorly understood. Methods We analyzed by transmission electron microscopy endocytosis and intracellular localization of NBTXR3 nanoparticles after endocytosis in various cell lines, in vitro and in vivo. A kinetic of NBTXR3 endocytosis and its impact on lysosomes was conducted using LysoTracker staining, and a RNAseq analysis was performed. We investigated the ability of NBTXR3 + RT to induce lysosomal membrane permeabilization (LMP) and ferroptosis by analyzing lipid peroxidation. Additionally, we evaluated the recapture by cancer cells of NBTXR3 released from dead cells. Results NBTXR3 nanoparticles were rapidly internalized by cells mainly through macropinocytosis and in a less extend by clathrin-dependent endocytosis. NBTXR3-containing endosomes were then fused with lysosomes. The day following NBTXR3 addition, we measured a significant increase in LysoTracker lysosome labeling intensity, in vitro as in vivo. Following RT, a significant lysosomal membrane permeabilization (LMP) was measured exclusively in cells treated with NBTXR3 + RT, while RT had no effect. The day post-irradiation, a significant increase in lipid peroxidation, a biomarker of ferroptosis, was measured with NBTXR3 + RT compared to RT. Moreover, we demonstrated that NBTXR3 nanoparticles released from dead cells can be recaptured by cancer cells. Conclusions Our findings provide novel insights into the early and specific biological effects induced by NBTXR3 + RT, especially LMP, not induced by RT in our models. The subsequent significant increase in lipid peroxidation partially explains the enhanced cancer cell killing capacity of NBTXR3 + RT compared to RT, potentially by promoting ferroptosis. This study improves our understanding of the cellular mechanisms underlying NBTXR3 + RT and highlights its potential as an agnostic therapeutic strategy for solid cancers treatment. Graphical Abstract

show abstract

“…By analyzing the expression profile changes upon the knockdown of FTO expression in cells, we identified that some of the deregulated genes were involved in the regulation of lipoproteins, lipid transport, palmitate, and monooxygenase, all of which are hallmarks of ferroptosis. Previous studies have shown that radiotherapy directly induces ferroptosis by upregulating critical regulators of ferroptosis, including SLC7A11 and ACSL4, in cancer cells [32] . Thus, we explored the regulatory relationship between FTO and ferroptosis in NPC radioresistance.…”

Section: Discussionmentioning

confidence: 98%

m6A demethylase FTO renders radioresistance of nasopharyngeal carcinoma via promoting OTUB1-mediated anti-ferroptosis

Huang

et al. 2023

Translational Oncology

View full text Add to dashboard Cite

Contribution of Lipid Oxidation and Ferroptosis to Radiotherapy Efficacy

Cited by 18 publications

References 76 publications

Ferroptosis-Associated Molecular Features to Aid Patient Clinical Prognosis and Therapy Across Human Cancers

Ferroptosis-Associated Molecular Features to Aid Patient Clinical Prognosis and Therapy Across Human Cancers

Radiotherapy-activated NBTXR3 nanoparticles promote ferroptosis through induction of lysosomal membrane permeabilization

m6A demethylase FTO renders radioresistance of nasopharyngeal carcinoma via promoting OTUB1-mediated anti-ferroptosis

Contact Info

Product

Resources

About