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 IIS 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 FOXO1a 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.
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Research Article|
March 14 2012
The anti-neurodegenerative agent clioquinol regulates the transcription factor FOXO1a
Amy R. Cameron;
Amy R. Cameron
*Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, U.K.
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Katherine Wallace;
Katherine Wallace
*Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, U.K.
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Lisa Logie;
Lisa Logie
*Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, U.K.
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Alan R. Prescott;
Alan R. Prescott
†Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Terry G. Unterman;
Terry G. Unterman
‡Division of Endocrinology, Diabetes and Metabolism, University of Illinois College of Medicine at Chicago, Chicago, IL 60612, U.S.A.
§Jesse Brown Veterans Administration Medical Center, Chicago, IL 60612, U.S.A.
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Jean Harthill;
Jean Harthill
*Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, U.K.
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Graham Rena
Graham Rena
1
*Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, U.K.
1To whom correspondence should be addressed (email g.rena@dundee.ac.uk).
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Publisher: Portland Press Ltd
Received:
December 14 2011
Accepted:
January 16 2012
Accepted Manuscript online:
January 16 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 443 (1): 57–64.
Article history
Received:
December 14 2011
Accepted:
January 16 2012
Accepted Manuscript online:
January 16 2012
Citation
Amy R. Cameron, Katherine Wallace, Lisa Logie, Alan R. Prescott, Terry G. Unterman, Jean Harthill, Graham Rena; The anti-neurodegenerative agent clioquinol regulates the transcription factor FOXO1a. Biochem J 1 April 2012; 443 (1): 57–64. doi: https://doi.org/10.1042/BJ20112124
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