The discovery of regulated cell death processes has enabled advances in cancer treatment. In the past decade, ferroptosis, an iron-dependent form of regulated cell death driven by excessive lipid peroxidation, has been implicated in the development and therapeutic responses of various types of tumours. Experimental reagents (such as erastin and RSL3), approved drugs (for example, sorafenib, sulfasalazine, statins and artemisinin), ionizing radiation and cytokines (such as IFNγ and TGFβ1) can induce ferroptosis and suppress tumour growth. However, ferroptotic damage can trigger inflammation-associated immunosuppression in the tumour microenvironment, thus favouring tumour growth. The extent to which ferroptosis affects tumour biology is unclear, although several studies have found important correlations between mutations in cancer-relevant genes (for example, RAS and TP53), in genes encoding proteins involved in stress response pathways (such as NFE2L2 signalling, autophagy and hypoxia) and the epithelial-to-mesenchymal transition, and responses to treatments that activate ferroptosis. Herein, we present the key molecular mechanisms of ferroptosis, describe the crosstalk between ferroptosis and tumour-associated signalling pathways, and discuss the potential applications of ferroptosis in the context of systemic therapy, radiotherapy and immunotherapy. Ferroptosis is an iron-dependent form of regulated cell death driven by excessive lipid peroxidation. Pharmacological agents, ionizing radiation and cytokines can induce ferroptosis and thus suppress tumour growth, but ferroptosis can also trigger inflammation-associated immunosuppression. The authors describe the key molecular mechanisms of ferroptosis, including crosstalk with tumour-associated signalling pathways, and discuss potential therapeutic applications of ferroptosis.

Broadening horizons: the role of ferroptosis in cancer.

A double-edged sword.

Ferroptosis, a novel form of regulated cell death, is different from other types of cell death in morphology, genetics and biochemistry. Increasing evidence indicates that ferroptosis has significant implications on cell death linked to cardiomyopathy, tumorigenesis, and cerebral hemorrhage to name a few. Here we summarize current literature on ferroptosis, including organelle dysfunction, signaling transduction pathways, metabolic reprogramming and epigenetic regulators in cancer progression. With regard to organelles, mitochondria-induced cysteine starvation, endoplasmic reticulum-related oxidative stress, lysosome dysfunction and golgi stress-related lipid peroxidation all contribute to induction of ferroptosis. Understanding the underlying mechanism in ferroptosis could provide insight into the treatment of various intractable diseases including cancers.

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The epigenetic regulators and metabolic changes in ferroptosis-associated cancer progression.

Ferroptosis, an iron-dependent form of regulated cell death driven by peroxidative damages of polyunsaturated-fatty-acid-containing phospholipids in cellular membranes, has recently been revealed to play an important role in radiotherapy-induced cell death and tumor suppression, and to mediate the synergy between radiotherapy and immunotherapy. In this review, we summarize known as well as putative mechanisms underlying the crosstalk between radiotherapy and ferroptosis, discuss the interactions between ferroptosis and other forms of regulated cell death induced by radiotherapy, and explore combination therapeutic strategies targeting ferroptosis in radiotherapy and immunotherapy. This review will provide important frameworks for future investigations of ferroptosis in cancer therapy.

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Ferroptosis, radiotherapy, and combination therapeutic strategies

The hallmark of tumorigenesis is the successful circumvention of cell death regulation for achieving unlimited replication and immortality. Ferroptosis is a newly identified type of cell death dependent on lipid peroxidation which differs from classical programmed cell death in terms of morphology, physiology and biochemistry. The broad spectrum of injury and tumor tolerance are the main reasons for radiotherapy and chemotherapy failure. The effective rate of tumor immunotherapy as a new treatment method is less than 30%. Ferroptosis can be seen in radiotherapy, chemotherapy, and tumor immunotherapy; therefore, ferroptosis activation may be a potential strategy to overcome the drug resistance mechanism of traditional cancer treatments. In this review, the characteristics and causes of cell death by lipid peroxidation in ferroptosis are briefly described. In addition, the three metabolic regulations of ferroptosis and its crosstalk with classical signaling pathways are summarized. Collectively, these findings suggest the vital role of ferroptosis in immunotherapy based on the interaction of ferroptosis with tumor immunotherapy, chemotherapy and radiotherapy, thus, indicating the remarkable potential of ferroptosis in cancer treatment.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/cac2.12250

Ferroptosis in cancer and cancer immunotherapy

Glutathione peroxidase 4 (GPX4) has been confirmed to inhibit ferroptosis in cancer cells, however, whether GPX4 serves as an oncogene is not clear. In this study, the expression of GPX4 and its influence to survival of patients with cancer were analyzed via public databases. Furthermore, the epigenetic regulation of GPX4 and the relation between GPX4 and chemoresistance of different anticancer drugs was also detected. Most importantly, cytological assays were performed to investigate the function of GPX4 in cancer cells. The results showed that GPX4 was higher expressed in cancer tissues than normal and was negatively associated with prognosis of patients. Furthermore, at upstream of GPX4 there was low DNA methylation sites and enhanced level of H3K4me3 and H3K27ac, indicating that high level of GPX4 in cancer may resulted from epigenetic regulation. Moreover, GPX4 was positively related to chemoresistance of anticancer drugs L-685458, lapatinib, palbociclib, and topotecan. In addition, GPX4 may potentially be involved in translation of protein, mitochondrial respiratory chain complex I assembly, electron transport oxidative phosphorylation, nonalcoholic fatty liver disease, and metabolic pathways. Finally, we detected that GPX4 inhibited ferroptosis in cancer cells, the inhibition of GPX4 via RSL3 could enhance the anticancer effect of cisplatin in vitro and in vivo. In conclusion, GPX4 acts as an oncogene and inhibits ferroptosis in cancer cells, the anticancer effect of cisplatin can be enhanced by GPX4 inhibition.

Inhibition of tumor propellant glutathione peroxidase 4 induces ferroptosis in cancer cells and enhances anticancer effect of cisplatin

Cancer progression including proliferation, metastasis, and chemoresistance has become a serious hindrance to cancer therapy. This phenomenon mainly derives from the innate insensitive or acquired resistance of cancer cells to apoptosis. Ferroptosis is a newly discovered mechanism of programmed cell death characterized by peroxidation of the lipid membrane induced by reactive oxygen species. Ferroptosis has been confirmed to eliminate cancer cells in an apoptosis-independent manner, however, the specific regulatory mechanism of ferroptosis is still unknown. The use of ferroptosis for overcoming cancer progression is limited. Noncoding RNAs have been found to play an important roles in cancer. They regulate gene expression to affect biological processes of cancer cells such as proliferation, cell cycle, and cell death. Thus far, the functions of ncRNAs in ferroptosis of cancer cells have been examined, and the specific mechanisms by which noncoding RNAs regulate ferroptosis have been partially discovered. However, there is no summary of ferroptosis associated noncoding RNAs and their functions in different cancer types. In this review, we discuss the roles of ferroptosis-associated noncoding RNAs in detail. Moreover, future work regarding the interaction between noncoding RNAs and ferroptosis is proposed, the possible obstacles are predicted and associated solutions are put forward. This review will deepen our understanding of the relationship between noncoding RNAs and ferroptosis, and provide new insights in targeting noncoding RNAs in ferroptosis associated therapeutic strategies.

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Crosstalk between noncoding RNAs and ferroptosis: new dawn for overcoming cancer progression

Objective To investigate the diagnostic performance of the ADNEX model in the International Ovarian Tumor Analysis diagnostic models for ovarian tumors and further explore its application value in the staging of ovarian tumors. Methods A total of 224 patients who underwent ultrasound for evaluation of adnexal masses and were treated surgically owing to adnexal masses from January 2018 to June 2020 in our hospital were selected for research on the diagnostic accuracy of the ADNEX model. The clinical information and ultrasonographic findings of the patients were collected, and the pathological diagnosis was taken as the gold standard. According to the ADNEX model, the ovarian tumors were divided into five subtypes: benign and borderline, stage I, stage II-IV, and metastatic cancer. The sensitivity, specificity, positive predictive value, negative predictive value, diagnostic odds ratio, and area under the receiver operating characteristics curve (AUC) of the ADNEX model were calculated. Results Of the 224 patients, 119 (53.1%) developed benign tumors and 105 (46.9%) had malignant tumors. When the cut-off value for malignancy risk was 10%, the ADNEX model including CA 125 achieved a sensitivity of 94.3% (95% CI: 88.0-97.9%), specificity of 74.0% (95% CI: 65.1-81.6%), positive predictive value of 76.2% (95% CI: 70.2-81.3%), negative predictive value of 93.6% (95% CI: 87.0-97.0%), diagnostic odds ratio of 45.25, and an AUC of 0.94 (95% CI: 0.90-0.97) for differentiating between benign and malignant ovarian tumors. The AUC in the model excluding CA 125 was 0.93 (95% CI: 0.89-0.96), but the difference was not statistically significant (P=0.20). The accuracy of the ADNEX model for the diagnosis of ovarian tumors of all subtypes exceeds 80% when CA 125 measurements were included in the application, but the sensitivity for diagnosing borderline, stage I, and metastatic ovarian tumors was only 60.0% (95% CI:36.1-80.9%), 28.6% (95% CI:8.4-58.1%) and 45.5% (95% CI:16.7-76.6%). Conclusion The ADNEX model shows good diagnostic performance in differentiating between benign and malignant ovarian tumors. The model has a certain clinical value in the diagnosis of all subtypes of ovarian tumors, but the sensitivity is unsatisfactory for the diagnosis of borderline, stage I, and metastatic ovarian tumors and needs to be verified.

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Evaluation of the Diagnostic Value of the Ultrasound ADNEX Model for Benign and Malignant Ovarian Tumors

Ovarian cancer (OC) is a type of cancer with high prevalence and shocking mortality in women around the world. Radioresistance is a major reason for OC relapse. Mounting studies have shown the significant function of dysregulated microRNAs (miRNAs) in cancer progression and the cellular response to irradiation. The present study inquired about the function and mechanism of microRNA (miR)-4478 in regulating radiosensitivity of OC cells. Results showed that miR-4478 was downregulated in OC, and a low miR-4478 level indicated a disappointing prognosis for OC patients. Besides, in OC cells exposed to irradiation, the expression of miR-4478 decreased over time. Functionally, the upregulation of miR-4478 retarded OC cell proliferation and sensitized OC cells to irradiation. Mechanistically, miR-4478 targeted and inhibited fused in sarcoma (Fus). Additionally, Fus was upregulated in OC and its expression further elevated in OC cells under irradiation. Furthermore, miR-4478 targeted Fus to inhibit autophagy, therefore sensitizing OC cells to irradiation. Collectively, our study uncovered miR-4478 as a novel radiosensitizer by targeting Fus in OC cells, which may shed a new light on developing targets for treating patients with OC, particularly those with radioresistance.

miR-4478 sensitizes ovarian cancer cells to irradiation by inhibiting Fus and attenuating autophagy.

https://www.tandfonline.com/doi/pdf/10.1080/14686996.2020.1855064

Lingling Wang

Papers

Inhibition of tumor propellant glutathione peroxidase 4 induces ferroptosis in cancer cells and enhances anticancer effect of cisplatin

Crosstalk between noncoding RNAs and ferroptosis: new dawn for overcoming cancer progression

Evaluation of the Diagnostic Value of the Ultrasound ADNEX Model for Benign and Malignant Ovarian Tumors

miR-4478 sensitizes ovarian cancer cells to irradiation by inhibiting Fus and attenuating autophagy.

Cetuximab-conjugated perfluorohexane/gold nanoparticles for low intensity focused ultrasound diagnosis ablation of thyroid cancer treatment