Sprouty2 enhances the tumorigenic potential of glioblastoma cells

Park, Jong‐Whi; Wollmann, Guido; Urbiola, Carles; Fogli, Barbara; Florio, Tullio; Geley, Stephan; Klimaschewski, Lars

doi:10.1093/neuonc/noy028

Cited by 30 publications

(38 citation statements)

References 35 publications

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“…Recently, we corroborated an oncogenic role of Sprouty2 in glial brain tumors (Park et al, 2018). Its expression is up-regulated in highly malignant gliomas which correlates with reduced overall patient survival.…”

Section: Introductionsupporting

confidence: 78%

Subcellular Localization of Sprouty2 in Human Glioma Cells

Hausott

Park

Valovka

et al. 2019

Front. Mol. Neurosci.

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Sprouty proteins act ubiquitously as signaling integrators and inhibitors of receptor tyrosine kinase (RTK) activated pathways. Among the four Sprouty isoforms, Sprouty2 is a key regulator of growth factor signaling in several neurological disorders. High protein levels correlate with reduced survival of glioma patients. We recently demonstrated that abrogating its function inhibits tumor growth by overstimulation of ERK and induction of DNA replication stress. The important role of Sprouty2 in the proliferation of malignant glioma cells prompted us to investigate its subcellular localization applying super-resolution fluorescence and immunoelectron microscopy. We found that cytoplasmic Sprouty2 is not homogenously distributed but localized to small spots (<100 nm) partly attached to vimentin filaments and co-localized with activated ERK. The protein is associated with early, late and recycling endosomes in response to but also independently of growth factor stimulation. The subcellular localization of Sprouty2 in all areas exhibiting strong RTK activities may reflect a protective response of glioma cells to limit excessive ERK activation and to prevent cellular senescence and apoptosis.

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Section: Introductionsupporting

confidence: 78%

Subcellular Localization of Sprouty2 in Human Glioma Cells

Hausott

Park

Valovka

et al. 2019

Front. Mol. Neurosci.

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“…Sprouty2 expression is upregulated and is associated with poor prognosis in GBM patients . Sprouty2 promotes ERK activation, proliferation, and drug resistance in GBM . Moreover, Sprouty1 is induced by insulin‐like growth factor binding protein‐2 through the nuclear factor‐κB (NF‐κB) pathway, which might play an important role in maintenance of the mesenchymal phenotypes of GBM cells…”

Section: Roles Of Sprouty/spred During Tumorigenesis and Metastasismentioning

confidence: 99%

“…Sprouty2 expression is upregulated and is associated with poor prognosis in GBM patients . Sprouty2 promotes ERK activation, proliferation, and drug resistance in GBM .…”

Section: Roles Of Sprouty/spred During Tumorigenesis and Metastasismentioning

confidence: 99%

The Sprouty/Spred family as tumor suppressors: Coming of age

Kawazoe

Taniguchi

2019

Cancer Science

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The Ras/Raf/ERK pathway is one of the most frequently dysregulated signaling pathways in various cancers. In some such cancers, Ras and Raf are hotspots for mutations, which cause continuous activation of this pathway. However, in some other cancers, it is known that negative regulators of the Ras/Raf/ERK pathway are responsible for uncontrolled activation. The Sprouty/Spred family is broadly recognized as important negative regulators of the Ras/Raf/ERK pathway, and its expression is downregulated in many malignancies, leading to hyperactivation of the Ras/Raf/ERK pathway. After the discovery of this family, intensive research investigated the mechanism by which it suppresses the Ras/Raf/ERK pathway and its roles in developmental and pathophysiological processes. In this review, we discuss the complicated roles of the Sprouty/Spred family in tumor initiation, promotion, and progression and its future therapeutic potential.

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“…CSCs are able to differentiate giving origin to all the phenotypes composing the bulk of the different cell populations within the tumor. Thus, the presence of CSCs confers great cell heterogeneity to GBM and, importantly, resistance to chemo- and radio-therapy involving different molecular mechanisms ( Singh et al, 2004 ; Florio and Barbieri, 2012 ; Park et al, 2018 ). In fact, like normal stem cells, CSCs display high expression of DNA repairing enzymes and drug efflux transporters.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Chloride Intracellular Channel 1 (CLIC1) as Biguanide Class-Effect to Impair Human Glioblastoma Stem Cell Viability

et al. 2018

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The antidiabetic biguanide metformin exerts antiproliferative effects in different solid tumors. However, during preclinical studies, metformin concentrations required to induce cell growth arrest were invariably within the mM range, thus difficult to translate in a clinical setting. Consequently, the search for more potent metformin derivatives is a current goal for new drug development. Although several cell-specific intracellular mechanisms contribute to the anti-tumor activity of metformin, the inhibition of the chloride intracellular channel 1 activity (CLIC1) at G1/S transition is a key events in metformin antiproliferative effect in glioblastoma stem cells (GSCs). Here we tested several known biguanide-related drugs for the ability to affect glioblastoma (but not normal) stem cell viability, and in particular: phenformin, a withdrawn antidiabetic drug; moroxydine, a former antiviral agent; and proguanil, an antimalarial compound, all of them possessing a linear biguanide structure as metformin; moreover, we evaluated cycloguanil, the active form of proguanil, characterized by a cyclized biguanide moiety. All these drugs caused a significant impairment of GSC proliferation, invasiveness, and self-renewal reaching IC50 values significantly lower than metformin, (range 0.054–0.53 mM vs. 9.4 mM of metformin). All biguanides inhibited CLIC1-mediated ion current, showing the same potency observed in the antiproliferative effects, with the exception of proguanil which was ineffective. These effects were specific for GSCs, since no (or little) cytotoxicity was observed in normal umbilical cord mesenchymal stem cells, whose viability was not affected by metformin and moroxydine, while cycloguanil and phenformin induced toxicity only at much higher concentrations than required to reduce GSC proliferation or invasiveness. Conversely, proguanil was highly cytotoxic also for normal mesenchymal stem cells. In conclusion, the inhibition of CLIC1 activity represents a biguanide class-effect to impair GSC viability, invasiveness, and self-renewal, although dissimilarities among different drugs were observed as far as potency, efficacy and selectivity as CLIC1 inhibitors. Being CLIC1 constitutively active in GSCs, this feature is relevant to grant the molecules with high specificity toward GSCs while sparing normal cells. These results could represent the basis for the development of novel biguanide-structured molecules, characterized by high antitumor efficacy and safe toxicological profile.

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Sprouty2 enhances the tumorigenic potential of glioblastoma cells

Cited by 30 publications

References 35 publications

Subcellular Localization of Sprouty2 in Human Glioma Cells

Subcellular Localization of Sprouty2 in Human Glioma Cells

The Sprouty/Spred family as tumor suppressors: Coming of age

Inhibition of Chloride Intracellular Channel 1 (CLIC1) as Biguanide Class-Effect to Impair Human Glioblastoma Stem Cell Viability

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