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  • 1
    Online-Ressource
    Online-Ressource
    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
    Kurzfassung: 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.
    Materialart: Online-Ressource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-17-1223
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2018
    ZDB Id: 2062135-8
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
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    Online-Ressource
    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
    Kurzfassung: 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.
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-2549
    RVK:
    XA 36000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2019
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
    Online-Ressource
    Online-Ressource
    Abstract 2938: Transmembrane chloride intracellular channel 1 (tmCLIC1) correlates with metastatic potential of colorectal cancer cells
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2938-2938
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2938-2938
    Kurzfassung: Colorectal cancer (CRC) is the third most common and lethal tumor worldwide. Although CRC can be efficiently eradicated when diagnosed in the early stage, no effective therapies are currently available for advanced metastatic disease. Therefore, targeting metastasis represents a critical challenge for the successful treatment of CRC. To achieve this purpose, our laboratory has found a promising candidate inthe transmembrane localized Chloride Intracellular Channel 1 (tmCLIC1) protein. Growing scientific evidence have suggested an involvement of tmCLIC1 in different human malignancies, including CRC, with an unknown mechanism. CLIC1 is a metamorphic protein able to shuttle between a soluble cytoplasmic and a membrane integrated form, the latter characterized by ionic channel function. In normal cells, it is mostly cytoplasmic and cooperates to the maintenance of several physiological processes. Otherwise, in cancer cells CLIC1 undergoes to chronic membrane insertion, where contributes to the abnormal cellular hyperproliferative rate.In the present investigation, using CRC human cell lines at different stage of tumor development, we demonstrate that tmCLIC1 functional expression correlates with CRC cells increasing aggressiveness, while it is almost absent in normal colon cells. We also show that CLIC1 enrichment in plasma membrane is involved in promotion of CRC metastasis. CLIC1 inhibition using different pharmacological treatments led to drastic reduction of cell proliferation, migration and invasiveness.tmCLIC1 function permits to discriminate between normal and malignant cells and its downregulation is able to arrest metastatic cells. This is not the case of other upregulated proteins not only involved in tumorigenesis but also in physiological cell functions. Since metastasis are considered the leading cause of treatment failure and tumor relapse, CLIC1 inhibition coupled to conventional therapies can represent a novel strategy to successfully treat CRC with reduced side effects. (This work is supported by a GRANT from AIRC to MM) Citation Format: Valentina Carlini, Francesca Cianci, Ivan Verduci, Michele Mazzanti. Transmembrane chloride intracellular channel 1 (tmCLIC1) correlates with metastatic potential of colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philad elphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2938.
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-2938
    RVK:
    XA 36000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2019
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 4
    Online-Ressource
    Online-Ressource
    Repurposed Biguanide Drugs in Glioblastoma Exert Antiproliferative Effects via the Inhibition of Intracellular Chloride Channel 1 Activity
    Frontiers Media SA ; 2019
    In:  Frontiers in Oncology Vol. 9 ( 2019-3-13)
    Details
    In: Frontiers in Oncology, Frontiers Media SA, Vol. 9 ( 2019-3-13)
    Materialart: Online-Ressource
    ISSN: 2234-943X
    URL: Article
    DOI: 10.3389/fonc.2019.00135
    Sprache: Unbekannt
    Verlag: Frontiers Media SA
    Publikationsdatum: 2019
    ZDB Id: 2649216-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
    Online-Ressource
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    Abstract 304: CLIC1 membrane insertion is a pivotal regulator of glioblastoma stem cell G1-S transition by promoting an increase of chloride permeability
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 304-304
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 304-304
    Kurzfassung: Glioblastoma (GBM) is the most aggressive and lethal brain tumor and, despite aggressive surgery and adjuvant radiotherapy and/or chemotherapy, the prognosis remains invariantly poor. As for most of solid and hematological malignancies, it was demonstrated that the bulk of tumor cells in GBM is generated by a rare fraction of self-renewing, multipotent cancer stem cells (CSCs) and the persistence of CSCs within the tumor mass is considered the main determinant of GBM development, progression, recurrence and radio- or chemoresistance. Thus, one of the main goals of current research is to identify specific biological mechanisms or intracellular pathways of CSCs whose pharmacological targeting might affect their survival and proliferation. In particular, little is known about the possibility that the molecular mechanisms underlying cell-cycle control in GBM CSCs are endowed with specific and unique features as compared with normal cells. Our study is based on the observation that GBM cells express higher levels of chloride intracellular channel 1 (CLIC1) as compared to nonmalignant brain cells and that in CSCs CLIC1 is mainly localized in the membrane forming an active channel. Conversely, in physiological conditions CLIC1 is mainly a cytoplasmic protein only transiently translocating to the membrane. We recently showed that the different level of activity of CLIC1 in CSCs and normal mesenchymal stem cells confers CLIC1-targeting drugs (for example the biguanide metformin) selective cytotoxicity toward tumor cells. Here we report, that in response to stress conditions, CLIC1 increases the probability to modify its structure going from a cytoplasmic hydrophilic form to a transmembrane conformation. Once in the membrane, CLIC1 acts as a chloride permeability, participating, together with NADPH oxidase, to the generation of a chronic state of oxidative stress that favor the transition between G1 and S phase. The peculiarity of CLIC1 exposure on the external face of the GMB CSC plasma membrane support the idea that this protein could represent a main determinant of the cell cycle progression in this tumor cell subpopulation and thus an accessible and relevant pharmacological target to eradicate CSCs in GBM. Note: This abstract was not presented at the meeting. Citation Format: Ivan Verduci, Valentina Carlini, Federica M. Raciti, Matteo Conti, Federica Barbieri, Tullio Florio, Michele Mazzanti. CLIC1 membrane insertion is a pivotal regulator of glioblastoma stem cell G1-S transition by promoting an increase of chloride permeability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 304. doi:10.1158/1538-7445.AM2017-304
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-304
    RVK:
    XA 36000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2017
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 6
    Online-Ressource
    Online-Ressource
    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
    Kurzfassung: 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.
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-4299
    RVK:
    XA 36000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2018
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 7
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    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)
    Materialart: Online-Ressource
    ISSN: 1663-9812
    URL: Article
    URL: Article
    DOI: 10.3389/fphar.2018.00899
    DOI: 10.3389/fphar.2018.00899.s001
    Sprache: Unbekannt
    Verlag: Frontiers Media SA
    Publikationsdatum: 2018
    ZDB Id: 2587355-6
    SSG: 15,3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 8
    Online-Ressource
    Online-Ressource
    Antiestrogen- and tamoxifen-induced effects on calcium-activated chloride currents in epithelial cells carrying the ∆F508-CFTR point mutation
    Springer Science and Business Media LLC ; 2018
    In:  Respiratory Research Vol. 19, No. 1 ( 2018-12)
    Details
    In: Respiratory Research, Springer Science and Business Media LLC, Vol. 19, No. 1 ( 2018-12)
    Materialart: Online-Ressource
    ISSN: 1465-993X
    URL: Article
    DOI: 10.1186/s12931-018-0901-1
    Sprache: Englisch
    Verlag: Springer Science and Business Media LLC
    Publikationsdatum: 2018
    ZDB Id: 2041675-1
    Standort Signatur Einschränkungen Verfügbarkeit
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