The anti-neurodegenerative agent clioquinol regulates the transcription factor FOXO1a

Amy R. Cameron, Katherine Wallace, Lisa Logie, Alan R. Prescott, Terry G. Unterman, Jean Harthill, Graham Rena (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    6 Citations (Scopus)

    Abstract

    Many diseases of aging including AD (Alzheimer's disease) and T2D (Type 2 diabetes) are strongly associated with common risk factors, suggesting that there may be shared aging mechanisms underlying these diseases, with the scope to identify common cellular targets for therapy. In the present study we have examined the insulin-like signalling properties of an experimental AD 8-hydroxyquinoline drug known as CQ (clioquinol). The IIS [insulin/IGF-1 (insulin-like growth factor-1) signalling] kinase Akt/PKB (protein kinase B) inhibits the transcription factor FOXO1a (forkhead box O1a) by phosphorylating it on residues that trigger its exit from the nucleus. In HEK (human embryonic kidney)-293 cells, we found that CQ treatment induces similar responses. A key transcriptional response to US is the inhibition of hepatic gluconeogenic gene expression, and, in rat liver cells, CQ represses expression of the key gluconeogenic regulatory enzymes PEPCK (phosphoenolpyruvate carboxykinase) and G6Pase (glucose-6-phosphatase). The effects on FOXO1. a and gluconeogenic gene expression require the presence of Zn2+ ions, reminiscent of much earlier studies examining diabetogenic properties of 8-hydroxyquinolines. Comparative investigation of the signalling properties of a panel of these compounds demonstrates that CQ alone exhibits FOXO1a regulation without diabetogenicity. Our results suggest that Zn2+-dependent regulation of FOXOs and gluconeogenesis may contribute to the therapeutic properties of this drug. Further investigation of this signalling response might illuminate novel pharmacological strategies for the treatment of age-related diseases.

    Original languageEnglish
    Pages (from-to)57-64
    Number of pages8
    JournalBiochemical Journal
    Volume443
    Issue number1
    DOIs
    Publication statusPublished - 1 Apr 2012

    Cite this

    Cameron, Amy R. ; Wallace, Katherine ; Logie, Lisa ; Prescott, Alan R. ; Unterman, Terry G. ; Harthill, Jean ; Rena, Graham. / The anti-neurodegenerative agent clioquinol regulates the transcription factor FOXO1a. In: Biochemical Journal. 2012 ; Vol. 443, No. 1. pp. 57-64.
    @article{4a36ecad90ad44fd8f116ff1c0a8f38f,
    title = "The anti-neurodegenerative agent clioquinol regulates the transcription factor FOXO1a",
    abstract = "Many diseases of aging including AD (Alzheimer's disease) and T2D (Type 2 diabetes) are strongly associated with common risk factors, suggesting that there may be shared aging mechanisms underlying these diseases, with the scope to identify common cellular targets for therapy. In the present study we have examined the insulin-like signalling properties of an experimental AD 8-hydroxyquinoline drug known as CQ (clioquinol). The IIS [insulin/IGF-1 (insulin-like growth factor-1) signalling] kinase Akt/PKB (protein kinase B) inhibits the transcription factor FOXO1a (forkhead box O1a) by phosphorylating it on residues that trigger its exit from the nucleus. In HEK (human embryonic kidney)-293 cells, we found that CQ treatment induces similar responses. A key transcriptional response to US is the inhibition of hepatic gluconeogenic gene expression, and, in rat liver cells, CQ represses expression of the key gluconeogenic regulatory enzymes PEPCK (phosphoenolpyruvate carboxykinase) and G6Pase (glucose-6-phosphatase). The effects on FOXO1. a and gluconeogenic gene expression require the presence of Zn2+ ions, reminiscent of much earlier studies examining diabetogenic properties of 8-hydroxyquinolines. Comparative investigation of the signalling properties of a panel of these compounds demonstrates that CQ alone exhibits FOXO1a regulation without diabetogenicity. Our results suggest that Zn2+-dependent regulation of FOXOs and gluconeogenesis may contribute to the therapeutic properties of this drug. Further investigation of this signalling response might illuminate novel pharmacological strategies for the treatment of age-related diseases.",
    author = "Cameron, {Amy R.} and Katherine Wallace and Lisa Logie and Prescott, {Alan R.} and Unterman, {Terry G.} and Jean Harthill and Graham Rena",
    year = "2012",
    month = "4",
    day = "1",
    doi = "10.1042/BJ20112124",
    language = "English",
    volume = "443",
    pages = "57--64",
    journal = "Biochemical Journal",
    issn = "0264-6021",
    publisher = "Portland Press",
    number = "1",

    }

    The anti-neurodegenerative agent clioquinol regulates the transcription factor FOXO1a. / Cameron, Amy R.; Wallace, Katherine; Logie, Lisa; Prescott, Alan R.; Unterman, Terry G.; Harthill, Jean; Rena, Graham (Lead / Corresponding author).

    In: Biochemical Journal, Vol. 443, No. 1, 01.04.2012, p. 57-64.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - The anti-neurodegenerative agent clioquinol regulates the transcription factor FOXO1a

    AU - Cameron, Amy R.

    AU - Wallace, Katherine

    AU - Logie, Lisa

    AU - Prescott, Alan R.

    AU - Unterman, Terry G.

    AU - Harthill, Jean

    AU - Rena, Graham

    PY - 2012/4/1

    Y1 - 2012/4/1

    N2 - Many diseases of aging including AD (Alzheimer's disease) and T2D (Type 2 diabetes) are strongly associated with common risk factors, suggesting that there may be shared aging mechanisms underlying these diseases, with the scope to identify common cellular targets for therapy. In the present study we have examined the insulin-like signalling properties of an experimental AD 8-hydroxyquinoline drug known as CQ (clioquinol). The IIS [insulin/IGF-1 (insulin-like growth factor-1) signalling] kinase Akt/PKB (protein kinase B) inhibits the transcription factor FOXO1a (forkhead box O1a) by phosphorylating it on residues that trigger its exit from the nucleus. In HEK (human embryonic kidney)-293 cells, we found that CQ treatment induces similar responses. A key transcriptional response to US is the inhibition of hepatic gluconeogenic gene expression, and, in rat liver cells, CQ represses expression of the key gluconeogenic regulatory enzymes PEPCK (phosphoenolpyruvate carboxykinase) and G6Pase (glucose-6-phosphatase). The effects on FOXO1. a and gluconeogenic gene expression require the presence of Zn2+ ions, reminiscent of much earlier studies examining diabetogenic properties of 8-hydroxyquinolines. Comparative investigation of the signalling properties of a panel of these compounds demonstrates that CQ alone exhibits FOXO1a regulation without diabetogenicity. Our results suggest that Zn2+-dependent regulation of FOXOs and gluconeogenesis may contribute to the therapeutic properties of this drug. Further investigation of this signalling response might illuminate novel pharmacological strategies for the treatment of age-related diseases.

    AB - Many diseases of aging including AD (Alzheimer's disease) and T2D (Type 2 diabetes) are strongly associated with common risk factors, suggesting that there may be shared aging mechanisms underlying these diseases, with the scope to identify common cellular targets for therapy. In the present study we have examined the insulin-like signalling properties of an experimental AD 8-hydroxyquinoline drug known as CQ (clioquinol). The IIS [insulin/IGF-1 (insulin-like growth factor-1) signalling] kinase Akt/PKB (protein kinase B) inhibits the transcription factor FOXO1a (forkhead box O1a) by phosphorylating it on residues that trigger its exit from the nucleus. In HEK (human embryonic kidney)-293 cells, we found that CQ treatment induces similar responses. A key transcriptional response to US is the inhibition of hepatic gluconeogenic gene expression, and, in rat liver cells, CQ represses expression of the key gluconeogenic regulatory enzymes PEPCK (phosphoenolpyruvate carboxykinase) and G6Pase (glucose-6-phosphatase). The effects on FOXO1. a and gluconeogenic gene expression require the presence of Zn2+ ions, reminiscent of much earlier studies examining diabetogenic properties of 8-hydroxyquinolines. Comparative investigation of the signalling properties of a panel of these compounds demonstrates that CQ alone exhibits FOXO1a regulation without diabetogenicity. Our results suggest that Zn2+-dependent regulation of FOXOs and gluconeogenesis may contribute to the therapeutic properties of this drug. Further investigation of this signalling response might illuminate novel pharmacological strategies for the treatment of age-related diseases.

    UR - http://www.scopus.com/inward/record.url?scp=84858307296&partnerID=8YFLogxK

    U2 - 10.1042/BJ20112124

    DO - 10.1042/BJ20112124

    M3 - Article

    VL - 443

    SP - 57

    EP - 64

    JO - Biochemical Journal

    JF - Biochemical Journal

    SN - 0264-6021

    IS - 1

    ER -