TRIM7 modulates NCOA4-mediated ferritinophagy and ferroptosis in glioblastoma cells

Li, Kaiqiang; Chen, Bingyu; Xu, Ai-Bo; Shen, Jing-Lan; Li, Kaixuan; Hao, Ke; Hao, Rongrong; Yang, Wenjun; Jiang, Wanli; Zheng, Yang; Ge, Feihang; Wang, Zhen

doi:10.1016/j.redox.2022.102451

Cited by 53 publications

(29 citation statements)

References 69 publications

(102 reference statements)

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“…For this purpose, we examined lipid peroxidation, a well‐known inducer for ferroptosis [49], by flow cytometry in MB cells, and observed that FANCD2 knockdown significantly increased lipid peroxidation (Figure 4E and supplementary material, Figure S3C). In addition, FANCD2 knockdown caused an increase in malondialdehyde (MDA; Figure 4F), a by‐product of ferroptosis, and a decrease in reduced glutathione (GSH; Figure 4G), a negative regulator of ferroptosis in vivo [50]. However, liproxstatin‐1, a ferroptosis inhibitor, reversed FANCD2 knockdown‐induced suppression on MB cell viability (Figure 4H ) .…”

Section: Resultsmentioning

confidence: 99%

FANCD2 deficiency sensitizes SHH medulloblastoma to radiotherapy via ferroptosis

Zhou,

Wang,

et al. 2024

The Journal of Pathology

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Radiotherapy is one of the standard therapeutic regimens for medulloblastoma (MB). Tumor cells utilize DNA damage repair (DDR) mechanisms to survive and develop resistance during radiotherapy. It has been found that targeting DDR sensitizes tumor cells to radiotherapy in several types of cancer, but whether and how DDR pathways are involved in the MB radiotherapy response remain to be determined. Single‐cell RNA sequencing was carried out on 38 MB tissues, followed by expression enrichment assays. Fanconi anemia group D2 gene (FANCD2) expression was evaluated in MB samples and public MB databases. The function of FANCD2 in MB cells was examined using cell counting assays (CCK‐8), clone formation, lactate dehydrogenase activity, and in mouse orthotopic models. The FANCD2‐related signaling pathway was investigated using assays of peroxidation, a malondialdehyde assay, a reduced glutathione assay, and using FerroOrange to assess intracellular iron ions (Fe2+). Here, we report that FANCD2 was highly expressed in the malignant sonic hedgehog (SHH) MB subtype (SHH‐MB). FANCD2 played an oncogenic role and predicted worse prognosis in SHH‐MB patients. Moreover, FANCD2 knockdown markedly suppressed viability, mobility, and growth of SHH‐MB cells and sensitized SHH‐MB cells to irradiation. Mechanistically, FANCD2 deficiency led to an accumulation of Fe2+ due to increased divalent metal transporter 1 expression and impaired glutathione peroxidase 4 activity, which further activated ferroptosis and reduced proliferation of SHH‐MB cells. Using an orthotopic mouse model, we observed that radiotherapy combined with silencing FANCD2 significantly inhibited the growth of SHH‐MB cell‐derived tumors in vivo. Our study revealed FANCD2 as a potential therapeutic target in SHH‐MB and silencing FANCD2 could sensitize SHH‐MB cells to radiotherapy via inducing ferroptosis. © 2024 The Pathological Society of Great Britain and Ireland.

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Section: Resultsmentioning

confidence: 99%

FANCD2 deficiency sensitizes SHH medulloblastoma to radiotherapy via ferroptosis

Zhou,

Wang,

et al. 2024

The Journal of Pathology

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“…So, another important conclusion of our work is the fact that HO-1 exerted antioxidant effects against DHA-induced ferroptosis. On the other hand, it had been reported that DOX could downregulate Nrf2 to inhibit HO-1 and GPX4 levels (Li et al, 2022a), which may be one of the important reasons for its synergism with DHA to induce ferroptosis. The combination of DHA and HO-1 inhibitors may have a potential application in cancer therapy by mediating the induction of ferroptosis.…”

Section: Discussionmentioning

confidence: 99%

Susceptibility of cervical cancer to dihydroartemisinin-induced ferritinophagy-dependent ferroptosis

Shi

Xiong

Yan

et al. 2023

Front. Mol. Biosci.

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The clinical therapeutics of cervical cancer is limited due to the drug resistance and metastasis of tumor. As a novel target for antitumor therapy, ferroptosis is deemed to be more susceptible for those cancer cells with resistance to apoptosis and chemotherapy. Dihydroartemisinin (DHA), the primary active metabolites of artemisinin and its derivatives, has exhibited a variety of anticancer properties with low toxicity. However, the role of DHA and ferroptosis in cervical cancer remained unclear. Here, we showed that DHA could time-dependently and dose-dependently inhibit the proliferation of cervical cancer cells, which could be alleviated by the inhibitors of ferroptosis rather than apoptosis. Further investigation confirmed that DHA treatment initiated ferroptosis, as evidenced by the accumulation of reactive oxygen species (ROS), malondialdehyde (MDA) and liquid peroxidation (LPO) levels and simultaneously depletion of glutathione peroxidase 4 (GPX4) and glutathione (GSH). Moreover, nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy was also induced by DHA leading to subsequent increases of intracellular labile iron pool (LIP), exacerbated the Fenton reaction resulting in excessive ROS production, and enhanced cervical cancer ferroptosis. Among them, we unexpectedly found that heme oxygenase-1 (HO-1) played an antioxidant role in DHA-induced cell death. In addition, the results of synergy analysis showed that the combination of DHA and doxorubicin (DOX) emerged a highly synergistic lethal effect for cervical cancer cells, which was related also to ferroptosis. Overall, our data revealed the molecular mechanisms that DHA triggered ferritinophagy-dependent ferroptosis and sensitized to DOX in cervical cancer, which may provide novel avenues for future therapy development.

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“…Amentoflavone induces ferroptosis in glioma cells though ATG7-mediated autophagy to break iron homeostasis (55). Interestingly, both coatomer protein complex subunit zeta 1 (COPZ1) and tripartite motif containing 7 (TRIM7) are associated with ferroptosis by regulating intracellular iron metabolism in GBM (57,59). Genetic inhibition of COPZ1 or TRIM7 suppresses tumor growth in vitro and in vivo, mechanistically by inducing NCOA4 expression and promoting ferritinophagy, followed by increased intracellular levels of ferrous iron and ultimately ferroptosis (57,59).…”

Section: Targeting Autophagy-dependent Ferroptosis Signaling Network ...mentioning

confidence: 99%

“…Interestingly, both coatomer protein complex subunit zeta 1 (COPZ1) and tripartite motif containing 7 (TRIM7) are associated with ferroptosis by regulating intracellular iron metabolism in GBM (57,59). Genetic inhibition of COPZ1 or TRIM7 suppresses tumor growth in vitro and in vivo, mechanistically by inducing NCOA4 expression and promoting ferritinophagy, followed by increased intracellular levels of ferrous iron and ultimately ferroptosis (57,59). More recently, multifunctional nanomaterials (including ultrasmall iron oxide nanoparticles and iron oxide nanoparticles loaded with paclitaxel) have the effects of increasing the intracellular iron level, catalyzing fenton reaction, generating ROS and lipid peroxidation, ultimately inducing ferroptosis via a BECN1dependent autophagy pathway (56,58).…”

Section: Targeting Autophagy-dependent Ferroptosis Signaling Network ...mentioning

confidence: 99%

Autophagy-dependent ferroptosis as a potential treatment for glioblastoma

et al. 2023

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Glioblastoma (GBM) is the most common malignant primary brain tumor with a poor 5-year survival rate. Autophagy is a conserved intracellular degradation system that plays a dual role in GBM pathogenesis and therapy. On one hand, stress can lead to unlimited autophagy to promote GBM cell death. On the other hand, elevated autophagy promotes the survival of glioblastoma stem cells against chemotherapy and radiation therapy. Ferroptosis is a type of lipid peroxidation-mediated regulated necrosis that initially differs from autophagy and other types of cell death in terms of cell morphology, biochemical characteristics, and the gene regulators involved. However, recent studies have challenged this view and demonstrated that the occurrence of ferroptosis is dependent on autophagy, and that many regulators of ferroptosis are involved in the control of autophagy machinery. Functionally, autophagy-dependent ferroptosis plays a unique role in tumorigenesis and therapeutic sensitivity. This mini-review will focus on the mechanisms and principles of autophagy-dependent ferroptosis and its emerging implications in GBM.

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TRIM7 modulates NCOA4-mediated ferritinophagy and ferroptosis in glioblastoma cells

Cited by 53 publications

References 69 publications

FANCD2 deficiency sensitizes SHH medulloblastoma to radiotherapy via ferroptosis

FANCD2 deficiency sensitizes SHH medulloblastoma to radiotherapy via ferroptosis

Susceptibility of cervical cancer to dihydroartemisinin-induced ferritinophagy-dependent ferroptosis

Autophagy-dependent ferroptosis as a potential treatment for glioblastoma

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