Ferroptosis Involvement in Glioblastoma Treatment

Mitre, Andrei-Otto; Florian, Alexandru Ioan; Buruiană, Andrei; Boer, Armand; Moldovan, Ioana Maria; Şoriţău, Olga; Florian, Ioan Ştefan; Şuşman, Sergiu

doi:10.3390/medicina58020319

Cited by 24 publications

(14 citation statements)

References 135 publications

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“…GBM, formerly known as pleomorphic glioblastoma, also called glioblastoma, is the most common primary malignant brain tumor [ 1 ]. It is caused by malignant transformation of astrocytomas and is the most malignant type of astrocytoma [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

[Retracted] N‐myc Downstream‐Regulated Gene 1 (NDRG1) Regulates Vascular Endothelial Growth Factor A (VEGFA) and Malignancies in Glioblastoma Multiforme (GBM)

Zhang

Chen

et al. 2022

BioMed Research International

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Background. NDRG1 has been reported to exhibit relatively low expression levels in glioma tissues compared with adjacent brain tissues. Additionally, NDRG1 is reported to be a tumor suppressor with the potential to suppress the proliferation, invasion, and migration of cancer cells. However, its exact roles in GBM are still unknown. Methods. Gene Expression Profiling Interactive Analysis (GEPIA) was employed to evaluate the expression level of NDRG1 in GBM. After the introduction of NDRG1, proliferation, analyses of colony formation, migration, and invasion capacities were performed. A luciferase reporter assay was performed to detect the effect of NDRG1 on the vascular endothelial growth factor A (VEGFA) promoter. Results. In this study, data from GBM and healthy individuals were retrospectively collected by employing GBM, and VEGFA was found to be differentially expressed in GBM tissues compared with adjacent brain tissues. Furthermore, NDRG1 expression is positively correlated with VEGFA expression, but not expression of the other two VEGF isoforms, VEGFB and VEGFC. In the glioma cell lines U87MG and U118, overexpression of NDRG1 significantly upregulated VEGFA. By performing a dual-luciferase reporter assay, it was observed that overexpressed NDRG1 transcriptionally activated VEGFA. Expectedly, overexpression of NDRG1 decreased cell viability by blocking cell cycle phases at G1 phase. Additionally, overexpression of NDRG1 inhibited invasion, colony formation, and tumor formation in soft agar. Remarkably, VEGFA silencing or blockade of VEGF receptor 2 (VEGFR2) further inhibited malignant behaviors in soft agar, including proliferation, invasion, colony formation, and tumor formation. Conclusions. NDRG1-induced VEGFA exerts protective effects in GBM via the VEGFA/VEGFR2 pathway. Therefore, targeting both NDRG1 and VEGFA may represent a novel therapy for the treatment of GBM.

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Section: Introductionmentioning

confidence: 99%

[Retracted] N‐myc Downstream‐Regulated Gene 1 (NDRG1) Regulates Vascular Endothelial Growth Factor A (VEGFA) and Malignancies in Glioblastoma Multiforme (GBM)

Zhang

Chen

et al. 2022

BioMed Research International

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“…ROS formation leads to lipid peroxidation (mainly phosphatidylethanolamine polyunsaturated fatty acids) that are destroying the lipid membranes, causing cell death. Ferroptosis is involved in several pathologies, including inflammatory pathologies, neurodegenerative diseases, cancers and I/R injuries (Liang et al, 2019;Capelletti et al, 2020;Reichert et al, 2020;Sun et al, 2020c;Mitre et al, 2022). In mice experimental models of I/R injury, ferroptosis inhibition reduces the intestinal ischemic area and also protects the lungs and liver against ischemia-induced remote injuries (Li et al, 2019bQiang et al, 2020;Deng et al, 2021).…”

Section: Ferroptosismentioning

confidence: 99%

miRNA Involvement in Cerebral Ischemia-Reperfusion Injury

et al. 2022

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Cerebral ischemia reperfusion injury is a debilitating medical condition, currently with only a limited amount of therapies aimed at protecting the cerebral parenchyma. Micro RNAs (miRNAs) are small, non-coding RNA molecules that via the RNA-induced silencing complex either degrade or prevent target messenger RNAs from being translated and thus, can modulate the synthesis of target proteins. In the neurological field, miRNAs have been evaluated as potential regulators in brain development processes and pathological events. Following ischemic hypoxic stress, the cellular and molecular events initiated dysregulate different miRNAs, responsible for long-terming progression and extension of neuronal damage. Because of their ability to regulate the synthesis of target proteins, miRNAs emerge as a possible therapeutic strategy in limiting the neuronal damage following a cerebral ischemic event. This review aims to summarize the recent literature evidence of the miRNAs involved in signaling and modulating cerebral ischemia-reperfusion injuries, thus pointing their potential in limiting neuronal damage and repair mechanisms. An in-depth overview of the molecular pathways involved in ischemia reperfusion injury and the involvement of specific miRNAs, could provide future perspectives in the development of neuroprotective agents targeting these specific miRNAs.

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“…GBM cells exhibit increased iron uptake and high free iron levels, implying their intrinsic predisposition to ferroptosis [ 10 , 11 ]. Moreover, recent studies have shown that in GBM promoting ferroptosis resulted in decreased tumor growth and treatment resistance [ 12 ]. These findings suggest that ferroptosis induction may be a potential modality, aiding the current post-operative treatments for GBM.…”

Section: Introductionmentioning

confidence: 99%

HIF-α activation by the prolyl hydroxylase inhibitor roxadustat suppresses chemoresistant glioblastoma growth by inducing ferroptosis

Xie

Zhang

et al. 2022

Cell Death Dis

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Patients with glioblastoma (GBM) have poor prognosis and limited treatment options, largely due to therapy resistance upon the induction of apoptosis. Ferroptosis emerges as a potential antineoplastic strategy to bypass apoptosis resistance in traditional therapeutics. Hypoxia is a fundamental hallmark of GBM and hypoxia-inducible factor (HIF) is the main regulator of hypoxia response, however, the role of HIF has not been sufficiently explored in GBM. Herein, we first discovered that amplifying HIF signals by the prolyl hydroxylase (PHD) inhibitor roxadustat significantly suppressed GBM cell growth in vitro and in vivo, especially when the cells were resistant to temozolomide (TMZ). The accumulation of lipid peroxidation and cellular iron in GBM cells following roxadustat treatment indicated that the cells underwent ferroptosis, which was also supported by morphological changes in mitochondrial ultrastructure and immunogenic signals release. Moreover, in vivo studies further confirmed the ferroptosis induction and verified that roxadustat significantly prolonged survival of the mice harboring chemoresistant GBM without visible organ toxicity. Finally, we proved that the ferroptosis induction by roxadustat is HIF-α independent, especially activation of HIF-2α upregulating lipid regulatory genes was revealed to be mainly responsible for the enhanced lipid peroxidation. Altogether, our study provided novel evidence that amplifying HIF signals induced ferroptosis in chemoresistant GBM cells and suppressed the tumor growth in vivo, highlighting that ferroptosis induction by targeting HIF-α might provide new approaches to improve GBM treatment.

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Ferroptosis Involvement in Glioblastoma Treatment

Cited by 24 publications

References 135 publications

[Retracted] N‐myc Downstream‐Regulated Gene 1 (NDRG1) Regulates Vascular Endothelial Growth Factor A (VEGFA) and Malignancies in Glioblastoma Multiforme (GBM)

[Retracted] N‐myc Downstream‐Regulated Gene 1 (NDRG1) Regulates Vascular Endothelial Growth Factor A (VEGFA) and Malignancies in Glioblastoma Multiforme (GBM)

miRNA Involvement in Cerebral Ischemia-Reperfusion Injury

HIF-α activation by the prolyl hydroxylase inhibitor roxadustat suppresses chemoresistant glioblastoma growth by inducing ferroptosis

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