Dataset Information

Radiation-Induced Lipid Peroxidation Triggers Ferroptosis and Synergizes with Ferroptosis Inducers.

ABSTRACT: Although radiation is widely used to treat cancers, resistance mechanisms often develop and involve activation of DNA repair and inhibition of apoptosis. Therefore, compounds that sensitize cancer cells to radiation via alternative cell death pathways are valuable. We report here that ferroptosis, a form of nonapoptotic cell death driven by lipid peroxidation, is partly responsible for radiation-induced cancer cell death. Moreover, we found that small molecules activating ferroptosis through system x_c^- inhibition or GPX4 inhibition synergize with radiation to induce ferroptosis in several cancer types by enhancing cytoplasmic lipid peroxidation but not increasing DNA damage or caspase activation. Ferroptosis inducers synergized with cytoplasmic irradiation, but not nuclear irradiation. Finally, administration of ferroptosis inducers enhanced the antitumor effect of radiation in a murine xenograft model and in human patient-derived models of lung adenocarcinoma and glioma. These results suggest that ferroptosis inducers may be effective radiosensitizers that can expand the efficacy and range of indications for radiation therapy.

SUBMITTER: Ye LF

PROVIDER: S-EPMC7180072 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Radiation-Induced Lipid Peroxidation Triggers Ferroptosis and Synergizes with Ferroptosis Inducers.

Ye Ling F LF Chaudhary Kunal R KR Zandkarimi Fereshteh F Harken Andrew D AD Kinslow Connor J CJ Upadhyayula Pavan S PS Dovas Athanassios A Higgins Dominique M DM Tan Hui H Zhang Yan Y Buonanno Manuela M Wang Tony J C TJC Hei Tom K TK Bruce Jeffrey N JN Canoll Peter D PD Cheng Simon K SK Stockwell Brent R BR

ACS chemical biology 20200114 2

Although radiation is widely used to treat cancers, resistance mechanisms often develop and involve activation of DNA repair and inhibition of apoptosis. Therefore, compounds that sensitize cancer cells to radiation via alternative cell death pathways are valuable. We report here that ferroptosis, a form of nonapoptotic cell death driven by lipid peroxidation, is partly responsible for radiation-induced cancer cell death. Moreover, we found that small molecules activating ferroptosis through sys ...[more]

PMID: 31899616

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Project description:Purpose: Gastric cancer remains one of the deadliest neoplasms worldwide, with a high need for new therapeutic options. Efficacies of targeted therapies are often limited owing to the inter- and intratumoral heterogeneity of gastric cancer. Thus, drugs with broader mechanisms of action rather than relying on the inhibition of a single specific oncogene are needed. Preclinical studies have identified histone deacetylases (HDAC) and their respective isoforms as potential therapeutic targets in gastric cancer. However, clinical efficacies are moderate and the mechanism(s) of action of HDAC inhibitors (HDACi) are only partially understood. Methods: In a panel of gastric cancer cell lines with different molecular characteristics, tumor cell inhibitory effects of different HDACi were studied. Lipid peroxidation levels were measured using flow cytometry. Proteome analysis was performed for the in-depth characterization of molecular alterations upon HDAC inhibition. HDACi effects on important ferroptosis genes were validated on the mRNA (RT-qPCR) and protein level (Western Blot). Results: Upon HDACi treatment, lipid peroxidation levels were found increased in all tested cell lines. Class-I HDACi (VK1, entinostat) showed the same toxicity profile as the pan-HDACi vorinostat. Proteome analysis revealed significant and concordant alterations in the expression of proteins related to ferroptosis induction. Key enzymes like ACSL4, POR or SLC7A11 showed distinct alterations in their expression patterns, providing an explanation for the increased lipid peroxidation. Alterations of POR and SLC7A11 levels upon treatment were also confirmed in primary human gastric cancer tissue cultures as relevant ex vivo model. Conclusion: We identify the induction of ferroptosis as a new mechanism of action of class-I HDACi in gastric cancer. Notably, these findings were independent of the genetic background of the cell lines, thus introducing HDAC inhibition as a more general therapeutic principle besides other, less broadly usable targeted drugs.

Dataset Information

Radiation-Induced Lipid Peroxidation Triggers Ferroptosis and Synergizes with Ferroptosis Inducers.

Publications

Radiation-Induced Lipid Peroxidation Triggers Ferroptosis and Synergizes with Ferroptosis Inducers.

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