Emerging mechanisms and applications of ferroptosis in the treatment of resistant cancers

Li, Bowen; Yang, Liang; Peng, Xueqiang; Fan, Qin; Wei, Shibo; Yang, Shuo; Li, Xinyu; Jin, Hongyuan; Wu, Bo; Huang, Mingyao; Tang, Shilei; Liu, Jingang; Li, Hangyu

doi:10.1016/j.biopha.2020.110710

Cited by 65 publications

(48 citation statements)

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“…6 a). Considering that NRF2 is an important regulator of the cellular ROS levels [ 28 , 29 ] and the accumulation of ROS is the trigger for ferroptosis [ 30 , 31 ], we validated cellular ROS levels and confirmed that (via DCFDA staining, details in Methods and Materials) NRF2 overexpression alleviated the total ROS levels induced by RT in ESCC cells (Additional file 1 : Figure S1a). In addition, we found that NRF2 overexpression significantly reduced RT-induced lipid peroxidation levels (analyzed by C11-BODIPY staining), as well as ferroptosis marker gene (PTGS2) expression (Fig.…”

Section: Resultsmentioning

confidence: 82%

“…Ferroptosis, a form of regulated cell death that is different from other forms of cell death, such as apoptosis and necrosis [ 48 ], is induced by excessive lipid peroxidation, and it serves as a natural mechanism for tumor inhibition. Targeting ferroptosis represents a promising strategy for cancer treatment, as it helps overcome tumor resistance [ 29 ]. The growing recognition of NRF2 as a modulator of ferroptosis indicates that it regulates the sensitivity of cancer treatment in specific types of cancer [ 49 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

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SLC7A11 regulated by NRF2 modulates esophageal squamous cell carcinoma radiosensitivity by inhibiting ferroptosis

et al. 2021

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Background Solute carrier family 7 member 11(SLC7A11) is a component of cysteine/glutamate transporter, which plays a key role in tumor growth; however, its underlying effect on radiosensitivity in esophageal squamous cell carcinoma (ESCC) remains unclear. This study aimed to clarify SLC7A11’s expression and correlation with nuclear expression of nuclear factor erythroid-2 (NRF2)-associated radioresistance in ESCC. Methods We included 127 ESCC patients who received radical chemoradiotherapy. Immunohistochemical staining was used to detect SLC7A11 and NRF2 nuclear expression, and the relationship between clinicopathological characteristics and survival rates or therapy response were evaluated. Western blot, dual-reporter assays and Chromatin immunoprecipitation (ChIP)-sequencing were used to analyze their relationship in vitro. Their roles in radioresistance were then investigated through multiple validation steps. Results NRF2 nuclear expression and SLC7A11 expression were overexpressed in ESCC tissues and were positively correlated with one another. NRF2 nuclear expression was significantly associated with tumor length, lymph node metastasis, and TNM stage, while SLC7A11 expression was associated with lymph node metastasis. Patients with high NRF2 nuclear expression and SLC7A11 expression had significantly shorter overall and progression-free survival, and poor treatment response. The multivariate model showed that NRF2 nuclear expression and SLC7A11 expression, sex and tumor location are independent prognostic factors. In vitro analysis confirmed that hyperactivation of NRF2 induced SLC7A11 expression by directly binding to its promoter region, promoting radioresistance, reducing radiotherapy-induced lipid peroxidation levels, PTGS2 expression, and radiotherapy-related ferroptosis morphologic features. Conclusion Our study reveals a connection between high SLC7A11 expression and NRF2 nuclear expression in patients with ESCC that was related to worse survival and poorer therapy outcomes. SLC7A11-mediated ferroptosis inhibition induced NRF2-associated radioresistance, highlighting potential of NRF2/SLC7A11/ferroptosis axis as future therapeutic targets against therapy resistance biomarker.

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Section: Resultsmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

SLC7A11 regulated by NRF2 modulates esophageal squamous cell carcinoma radiosensitivity by inhibiting ferroptosis

et al. 2021

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“…Currently, some clinical drugs, such as sorafenib, sulfasalazine, lanperisone, acetaminophen, and cisplatin, can induce ferroptosis in several types of cancer cells, supporting the feasibility of exploiting ferroptosis for the treatment of drug-resistant cancers (36,37). Genetic silencing of cystine/glutamate-induced ferroptosis in resistant head and neck cancer (HNC) cells enhanced sensitivity to cisplatin (38).…”

Section: Discussionmentioning

confidence: 99%

CISD2 Promotes Resistance to Sorafenib-Induced Ferroptosis by Regulating Autophagy in Hepatocellular Carcinoma

Wei

Yang

et al. 2021

Front. Oncol.

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PurposeSorafenib is a multi-kinase inhibitor that is used as a standard treatment for advanced hepatocellular carcinoma (HCC). However, the mechanism of sorafenib resistance in HCC is still unclear. It has been shown that CISD2 expression is related to the progression and poor prognosis of HCC. Here, we show a new role for CISD2 in sorafenib resistance in HCC.MethodsBioinformatic analysis was used to detect the expression of negative regulatory genes of ferroptosis in sorafenib-resistant samples. The concentration gradient method was used to establish sorafenib-resistant HCC cells. Western blot was used to detect the protein expression of CISD2, LC3, ERK, PI3K, AKT, mTOR, and Beclin1 in HCC samples. Quantitative real-time PCR (qPCR) was used to detect gene expression. CISD2 shRNA and Beclin1 shRNA were transfected to knock down the expression of the corresponding genes. Cell viability was detected by a CCK-8 assay. ROS were detected by DCFH-DA staining, and MDA and GSH were detected with a Lipid Peroxidation MDA Assay Kit and Micro Reduced Glutathione (GSH) Assay Kit, respectively. Flow cytometry was used to detect apoptosis and the levels of ROS and iron ions.ResultsCISD2 was highly expressed in HCC cells compared with normal cells and was associated with poor prognosis in patients. Knockdown of CISD2 promoted a decrease in the viability of drug-resistant HCC cells. CISD2 knockdown promoted sorafenib-induced ferroptosis in resistant HCC cells. The levels of ROS, MDA, and iron ions increased, but the change in GSH was not obvious. Knockdown of CISD2 promoted uncontrolled autophagy in resistant HCC cells. Inhibition of autophagy attenuated CISD2 knockdown-induced ferroptosis. The autophagy promoted by CISD2 knockdown was related to Beclin1. When CISD2 and Beclin1 were inhibited, the effect on ferroptosis was correspondingly weakened.ConclusionInhibition of CISD2 promoted sorafenib-induced ferroptosis in resistant cells, and this process promoted excessive iron ion accumulation through autophagy, leading to ferroptosis. The combination of CISD2 inhibition and sorafenib treatment is an effective therapeutic strategy for resistant HCC.

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“…Recent studies reported that therapy-resistant tumor cells were vulnerable to ferroptosis; therefore, ferroptosis induction will be a potential therapeutic method for tumors especially drug-resistant tumors ( Li B. et al, 2020 ; Jiang et al, 2021 ). Our study found that both SLC7A11 and GPX4 were overexpressed in CRC, and SLC7A11 was highly expressed in lung cancer by analyzing TIMER and Oncomine databases.…”

Section: Discussionmentioning

confidence: 99%

Prognostic and Immunological Role of Key Genes of Ferroptosis in Pan-Cancer

Shi

Hao

Fan

et al. 2021

Front. Cell Dev. Biol.

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Solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), and apoptosis inducing factor mitochondria associated 2 (AIFM2) are the key regulators in ferroptosis. However, the expression patterns and prognostic roles of these genes in pan-cancer are still largely unclear. The expression patterns and prognostic roles of SLC7A11, GPX4, and AIFM2 and the relationships between the expression levels of these genes and immune infiltration levels in pan-cancer were analyzed by using TIMER, gene expression profiling interactive analysis (GEPIA), Oncomine, and Kaplan–Meier databases. Our results showed that both SLC7A11 and GPX4 were overexpressed in colorectal cancer, and SLC7A11 was overexpressed in lung cancer. High levels of SLC7A11 and AIFM2 were significantly linked with the shortened disease-free survival and overall survival (OS) in adrenocortical carcinoma (ACC), respectively. And high expression of SLC7A11, GPX4, and AIFM2 were significantly correlated with the shortened OS of acute myeloid leukemia patients. In esophageal carcinoma (ESCA), GPX4 expression was significantly associated with the infiltration of macrophage and myeloid dendritic cell, and AIFM2 expression was significantly associated with the infiltration of CD4+ T cell. Importantly, GPX4 expression was positively correlated with the expression levels of monocyte markers (CD14 and CD115) and M2 macrophage markers (VSIG4 and MS4A4A) both in ESCA and in head and neck squamous cell carcinoma (HNSC). In summary, SLC7A11, GPX4, and AIFM2 are dysregulated in many types of cancers, and are candidate prognostic biomarkers for many types of cancers, and can be used to evaluate the infiltration of immune cells in tumor tissues.

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Emerging mechanisms and applications of ferroptosis in the treatment of resistant cancers

Cited by 65 publications

References 233 publications

SLC7A11 regulated by NRF2 modulates esophageal squamous cell carcinoma radiosensitivity by inhibiting ferroptosis

SLC7A11 regulated by NRF2 modulates esophageal squamous cell carcinoma radiosensitivity by inhibiting ferroptosis

CISD2 Promotes Resistance to Sorafenib-Induced Ferroptosis by Regulating Autophagy in Hepatocellular Carcinoma

Prognostic and Immunological Role of Key Genes of Ferroptosis in Pan-Cancer

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