Preferential Iron Trafficking Characterizes Glioblastoma Stem-like Cells

Schonberg, David L.; Miller, Tyler E.; Wu, Qiulian; Flavahan, William; Das, Nupur K.; Hale, James S.; Hubert, Christopher G.; Mack, Stephen C.; Jarrar, Awad; Karl, Robert T.; Rosager, Ann Mari; Nixon, Anne M.; Tesar, Paul J.; Hamerlik, Petra; Kristensen, Bjarne Winther; Horbinski, Craig; Connor, James R.; Fox, Paul L.; Lathia, Justin D.; Rich, Jeremy

doi:10.1016/j.ccell.2015.09.002

Cited by 272 publications

(318 citation statements)

References 55 publications

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“…In the US population, the two most common polymorphisms in HFE , H63D and C282Y , are seen in approximately 15% and 7% of the population, respectively [35]. Interestingly, recent work has also shown that the expression of TfR is a poor prognostic indicator in GBM, and that dysregulated iron metabolism including increased TfR expression and ferritin expression is associated with cancer stem cells in GBM [36] This suggests that the gene signature identified here is, at least in part, sorting cancers with more robust stem cell populations from cancers with fewer cancer stem cells.…”

Section: Discussionmentioning

confidence: 99%

Aberrations in the Iron Regulatory Gene Signature Are Associated with Decreased Survival in Diffuse Infiltrating Gliomas

et al. 2016

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Iron is a tightly regulated micronutrient with no physiologic means of elimination and is necessary for cell division in normal tissue. Recent evidence suggests that dysregulation of iron regulatory proteins may play a role in cancer pathophysiology. We use public data from The Cancer Genome Atlas (TCGA) to study the association between survival and expression levels of 61 genes coding for iron regulatory proteins in patients with World Health Organization Grade II-III gliomas. Using a feature selection algorithm we identified a novel, optimized subset of eight iron regulatory genes (STEAP3, HFE, TMPRSS6, SFXN1, TFRC, UROS, SLC11A2, and STEAP4) whose differential expression defines two phenotypic groups with median survival differences of 52.3 months for patients with grade II gliomas (25.9 vs. 78.2 months, p< 10−3), 43.5 months for patients with grade III gliomas (43.9 vs. 87.4 months, p = 0.025), and 54.0 months when considering both grade II and III gliomas (79.9 vs. 25.9 months, p < 10−5).

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Section: Discussionmentioning

confidence: 99%

Aberrations in the Iron Regulatory Gene Signature Are Associated with Decreased Survival in Diffuse Infiltrating Gliomas

et al. 2016

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“…7). Previous reports on ferritin-induced growth signaling described how glioblastoma cancer cells had high ferritin levels due to increased iron intake (10). In contrast, we demonstrate how cancer cells use an electrophilic oncometabolite to hijack ferritin regulation in an iron-independent mechanism to increase ferritin levels.…”

Section: Discussionmentioning

confidence: 42%

“…6F), indicating that ferritin can mediate growth in UOK262 cells. Previous reports indicated that FOXM1 was activated by ferritin through STAT3 signaling (10). Although UOK262-FH Ϫ/Ϫ cells had increased STAT3 phosphorylation relative to UOK262-FH res cells (see Fig.…”

Section: Resultsmentioning

confidence: 74%

“…Interestingly, both NRF2 and IRPs interplay to regulate the expression of the ferritin light chain (FTL) and the ferritin heavy chain (FTH1) genes (9). These genes encode different subunits of ferritin, which is a cellular iron storage protein recently shown to promote cancer cell proliferation (10). Specifically, NRF2 promotes FTL and FTH1 transcription, while IRP2 represses the translation of the resulting transcripts by binding to a hairpin structure located in the 5= untranslated region (UTR) known as an iron response element (IRE) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Ferritin confers a chronic growth signal by activating FOXM1 (Forkhead box protein M1) signaling (10). FOXM1 controls the expression of genes regulating progression through the G 2 /M phases of the cell cycle, and overexpression of FOXM1 is associated with cancer progression (14).…”

Section: Resultsmentioning

confidence: 99%

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Fumarate Mediates a Chronic Proliferative Signal in Fumarate Hydratase-Inactivated Cancer Cells by Increasing Transcription and Translation of Ferritin Genes

Kerins

Vashisht

Liang

et al. 2017

Molecular and Cellular Biology

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Germ line mutations of the gene encoding the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase (FH) cause a hereditary cancer syndrome known as hereditary leiomyomatosis and renal cell cancer (HLRCC). HLRCC-associated tumors harbor biallelic FH inactivation that results in the accumulation of the TCA cycle metabolite fumarate. Although it is known that fumarate accumulation can alter cellular signaling, if and how fumarate confers a growth advantage remain unclear. Here we show that fumarate accumulation confers a chronic proliferative signal by disrupting cellular iron signaling. Specifically, fumarate covalently modifies cysteine residues on iron regulatory protein 2 (IRP2), rendering it unable to repress ferritin mRNA translation. Simultaneously, fumarate increases ferritin gene transcription by activating the NRF2 (nuclear factor [erythroid-derived 2]-like 2) transcription factor. In turn, increased ferritin protein levels promote the expression of the promitotic transcription factor FOXM1 (Forkhead box protein M1). Consistently, clinical HLRCC tissues showed increased expression levels of both FOXM1 and its proliferation-associated target genes. This finding demonstrates how FH inactivation can endow cells with a growth advantage.KEYWORDS ferritin, FH, FOXM1, fumarate, HLRCC, NRF2 H ereditary leiomyomatosis and renal cell cancer (HLRCC) patients carry a germ line-inactivating mutation in one of the fumarate hydratase (FH) alleles and are prone to developing skin leiomyomas, uterine fibroids, and renal cell carcinoma of type 2 papillary morphology (1). HLRCC-associated tumors harbor a loss of heterozygosity at the FH locus, indicating biallelic FH inactivation as the tumor-initiating event (1). However, it remains unclear how FH inactivation drives carcinogenesis.The most direct consequence of FH inactivation is intracellular fumarate accumulation. Accumulated fumarate can covalently modify cysteine residues of proteins in an uncatalyzed process termed succination and cause many alterations in cellular signaling (2). Succination in HLRCC cells was first discovered on Kelch-like ECH-associated protein 1 (KEAP1), a negative regulator of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) transcription factor (3). Since HLRCC is driven by FH inactivation, chronic succination of KEAP1 results in constitutive NRF2 activation and increased expression of its target genes (3). Besides KEAP1, the Krebs cycle enzyme aconitase 2 (Aco2) was reported to be a succination target in Fh knockout mouse tissues, and succination inhibited its activity (2). Despite dramatic cellular changes induced by protein succina-

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Treatment of Glioblastoma Using Multicomponent Silica Nanoparticles

Turan

Bielecki

Perera

et al. 2019

Advanced Therapeutics

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Glioblastoma multiforme (GBM) remains highly lethal. This partially stems from the presence of brain tumor initiating cells (BTICs), a highly plastic cellular subpopulation that is resistant to current therapies. In addition to resistance, the blood-brain barrier limits the penetration of most drugs into GBMs. To effectively deliver a BTIC-specific inhibitor to brain tumors, a multicomponent nanoparticle, termed Fe@MSN, which contains a mesoporous silica shell and an iron oxide core, is developed. Fibronectin-targeting ligands direct the nanoparticle to the near-perivascular areas of GBM. After Fe@MSN particles are deposited in the tumor, an external low-power radiofrequency (RF) field triggers rapid drug release due to mechanical tumbling of the particle resulting in penetration of high amounts of drug across the blood-brain tumor interface and widespread drug delivery into the GBM. The nanoparticle is loaded with the drug 1400W, which is a potent inhibitor of the inducible nitric oxide synthase (iNOS). It is shown that iNOS is preferentially expressed in BTICs and is required for their maintenance. Using the 1400W-loaded Fe@MSN and RF-triggered release, in vivo studies indicate that the treatment disrupts the BTIC population in hypoxic niches, suppresses tumor growth and significantly increases survival in BTIC-derived GBM xenografts.

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Preferential Iron Trafficking Characterizes Glioblastoma Stem-like Cells

Cited by 272 publications

References 55 publications

Aberrations in the Iron Regulatory Gene Signature Are Associated with Decreased Survival in Diffuse Infiltrating Gliomas

Aberrations in the Iron Regulatory Gene Signature Are Associated with Decreased Survival in Diffuse Infiltrating Gliomas

Fumarate Mediates a Chronic Proliferative Signal in Fumarate Hydratase-Inactivated Cancer Cells by Increasing Transcription and Translation of Ferritin Genes

Treatment of Glioblastoma Using Multicomponent Silica Nanoparticles

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