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  • 1
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    Online Resource
    Mutual Influence of ROS, pH, and CLIC1 Membrane Protein in the Regulation of G1–S Phase Progression in Human Glioblastoma Stem Cells
    American Association for Cancer Research (AACR) ; 2018
    In:  Molecular Cancer Therapeutics Vol. 17, No. 11 ( 2018-11-01), p. 2451-2461
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 17, No. 11 ( 2018-11-01), p. 2451-2461
    Abstract: Glioblastoma (GB) is the most lethal, aggressive, and diffuse brain tumor. The main challenge for successful treatment is targeting the cancer stem cell (CSC) subpopulation responsible for tumor origin, progression, and recurrence. Chloride Intracellular Channel 1 (CLIC1), highly expressed in CSCs, is constitutively present in the plasma membrane where it is associated with chloride ion permeability. In vitro, CLIC1 inhibition leads to a significant arrest of GB CSCs in G1 phase of the cell cycle. Furthermore, CLIC1 knockdown impairs tumor growth in vivo. Here, we demonstrate that CLIC1 membrane localization and function is specific for GB CSCs. Mesenchymal stem cells (MSC) do not show CLIC1-associated chloride permeability, and inhibition of CLIC1 protein function has no influence on MSC cell-cycle progression. Investigation of the basic functions of GB CSCs reveals a constitutive state of oxidative stress and cytoplasmic alkalinization compared with MSCs. Both intracellular oxidation and cytoplasmic pH changes have been reported to affect CLIC1 membrane functional expression. We now report that in CSCs these three elements are temporally linked during CSC G1–S transition. Impeding CLIC1-mediated chloride current prevents both intracellular ROS accumulation and pH changes. CLIC1 membrane functional impairment results in GB CSCs resetting from an allostatic tumorigenic condition to a homeostatic steady state. In contrast, inhibiting NADPH oxidase and NHE1 proton pump results in cell death of both GB CSCs and MSCs. Our results show that CLIC1 membrane protein is crucial and specific for GB CSC proliferation, and is a promising pharmacologic target for successful brain tumor therapies. Mol Cancer Ther; 17(11); 2451–61. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-17-1223
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 2
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    Abstract 2549: Allostatic conditions in human glioblastoma stem cells are maintained with the contribution of CLIC1 membrane protein functional expression
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2549-2549
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2549-2549
    Abstract: Allostasis is a cellular condition physiologically occurring during transient hyper-activated state of the cell. When stress is persistent, cells are unable to restore a basal homeostatic state and allostasis become chronic. Most of the cells are not able to cope with these prolonged conditions and die. Conversely, solid tumors reveal a persistent stress state strengthen by chronic overexpression of several elements and hyper-activation of intracellular pathways. In glioblastoma stem cells (GSCs), the most evident allostatic outcome is a high rate of cell division. Several proteins present in the allostatic GSC plasma membrane are deregulated in either expression or function. Altering any of these proteins disrupts the allostatic equilibrium, causing drastic functional changes and, in some cases, cell death. Several of these proteins, potentially used as valuable pharmacological targets, are also crucial for the physiological activity of the cells. Consequently, modifying their functions would affect the survival of both cancer and healthy cell population. On the contrary, chloride intracellular protein 1 (CLIC1) is active as a membrane charge carrier only during periods of chronic stress, while during homeostatic conditions it is essentially irrelevant. Inhibition of NADPH oxidase or the NHE1 proton pump, both overexpressed in CSCs, causes death of both GSCs and normal mesenchymal stem cells. Conversely, impairing CLIC1 activity delays GSC cycle progression but leaves healthy cells functions unaltered. Our work suggests that CLIC1 protein and its associated chloride permeability are a crucial element involved in the stabilization of GB CSC allostasis. (This work is supported by a GRANT from AIRC to MM) Citation Format: Ivan Verduci, Valentina Carlini, Federica Barbieri, Antonio Daga, Tullio Florio, Michele Mazzanti. Allostatic conditions in human glioblastoma stem cells are maintained with the contribution of CLIC1 membrane protein functional expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2549.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-2549
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 3
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    Online Resource
    Abstract 4299: Mutual influence of ROS, pH and CLIC1 membrane protein in the regulation of G1/S phase progression in human glioblastoma stem cells
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 4299-4299
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 4299-4299
    Abstract: Glioblastoma (GB) is the most lethal, aggressive and diffuse brain tumor. The main challenge of successful treatment is targeting the cancer stem cell (CSC) sub-population responsible for tumor origin, progression and recurrence. Chloride Intracellular Channel 1 (CLIC1), highly expressed in CSCs, is constitutively present in the plasma membrane where it is associated with chloride ion permeability. In vitro, CLIC1 inhibition leads to a significant arrest of GB CSCs in G1 phase of the cell cycle. Furthermore, CLIC1 knockdown impairs tumor growth in vivo. Here we demonstrate that CLIC1 membrane localization and function is specific for GB CSCs. Mesenchymal stem cells (MSCs) do not show CLIC1-associated chloride permeability and inhibition of CLIC1 protein function has no influence on MSC cell cycle progression. Investigation of the basic functions of GB CSCs reveals a constitutive state of oxidative stress and cytoplasmic alkalinization compared with MSCs. We now report that these three elements are temporally linked during CSC G1/S transition. Impeding CLIC1-mediated chloride current prevents both intracellular ROS accumulation and pH changes. CLIC1 membrane functional impairment results in GB CSCs resetting from an allostatic tumorigenic condition to a homeostatic steady state. In contrast, inhibiting NADPH oxidase and the NHE1 proton pump results in cell death of both GB CSCs and MSCs. Our results show that CLIC1 membrane protein is crucial and specific for GB CSC proliferation, and is a promising pharmacological target for successful brain tumor therapies. This work was supported by grant n.16713, IG 2015 to MM Italian Association for Cancer Research (AIRC). Citation Format: Ivan Verduci, Marta Peretti, Federica Maddalena Raciti, Valentina Carlini, Alessandra Patarozzi, Sara Barozzi, Massimiliano Garrè, Sarah Sertic, Alex Costa, Antonio Daga, Federica Barbieri, Tullio Florio, Michele Mazzanti. Mutual influence of ROS, pH and CLIC1 membrane protein in the regulation of G1/S phase progression in human glioblastoma stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4299.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-4299
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
    Online Resource
    Online Resource
    Table_1.docx
    Frontiers Media SA ; 2018
    In:  Frontiers in Pharmacology Vol. 9 ( 2018-8-21)
    Details
    In: Frontiers in Pharmacology, Frontiers Media SA, Vol. 9 ( 2018-8-21)
    Type of Medium: Online Resource
    ISSN: 1663-9812
    URL: Article
    URL: Article
    DOI: 10.3389/fphar.2018.00899
    DOI: 10.3389/fphar.2018.00899.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2018
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    SSG: 15,3
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  • 5
    Online Resource
    Online Resource
    Chloride intracellular channel 1 activity is not required for glioblastoma development but its inhibition dictates glioma stem cell responsivity to novel biguanide derivatives
    Springer Science and Business Media LLC ; 2022
    In:  Journal of Experimental & Clinical Cancer Research Vol. 41, No. 1 ( 2022-02-08)
    Details
    In: Journal of Experimental & Clinical Cancer Research, Springer Science and Business Media LLC, Vol. 41, No. 1 ( 2022-02-08)
    Abstract: Chloride intracellular channel-1 (CLIC1) activity controls glioblastoma proliferation. Metformin exerts antitumor effects in glioblastoma stem cells (GSCs) inhibiting CLIC1 activity, but its low potency hampers its translation in clinical settings. Methods We synthesized a small library of novel biguanide-based compounds that were tested as antiproliferative agents for GSCs derived from human glioblastomas, in vitro using 2D and 3D cultures and in vivo in the zebrafish model. Compounds were compared to metformin for both potency and efficacy in the inhibition of GSC proliferation in vitro (MTT, Trypan blue exclusion assays, and EdU labeling) and in vivo (zebrafish model), migration (Boyden chamber assay), invasiveness (Matrigel invasion assay), self-renewal (spherogenesis assay), and CLIC1 activity (electrophysiology recordings), as well as for the absence of off-target toxicity (effects on normal stem cells and toxicity for zebrafish and chick embryos). Results We identified Q48 and Q54 as two novel CLIC1 blockers, characterized by higher antiproliferative potency than metformin in vitro, in both GSC 2D cultures and 3D spheroids. Q48 and Q54 also impaired GSC self-renewal, migration and invasion, and displayed low systemic in vivo toxicity. Q54 reduced in vivo proliferation of GSCs xenotransplanted in zebrafish hindbrain. Target specificity was confirmed by recombinant CLIC1 binding experiments using microscale thermophoresis approach. Finally, we characterized GSCs from GBMs spontaneously expressing low CLIC1 protein, demonstrating their ability to grow in vivo and to retain stem-like phenotype and functional features in vitro. In these GSCs, Q48 and Q54 displayed reduced potency and efficacy as antiproliferative agents as compared to high CLIC1-expressing tumors. However, in 3D cultures, metformin and Q48 (but not Q54) inhibited proliferation, which was dependent on the inhibition dihydrofolate reductase activity. Conclusions These data highlight that, while CLIC1 is dispensable for the development of a subset of glioblastomas , it acts as a booster of proliferation in the majority of these tumors and its functional expression is required for biguanide antitumor class-effects. In particular, the biguanide-based derivatives Q48 and Q54, represent the leads to develop novel compounds endowed with better pharmacological profiles than metformin, to act as CLIC1-blockers for the treatment of CLIC1-expressing glioblastomas, in a precision medicine approach.
    Type of Medium: Online Resource
    ISSN: 1756-9966
    URL: Article
    DOI: 10.1186/s13046-021-02213-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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