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 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.
authors.affiliation: Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK.
authors.forename: Amy R
authors.initials: AR
authors.lastname: Cameron
authors.forename: Katherine
authors.initials: K
authors.lastname: Wallace
authors.forename: Lisa
authors.initials: L
authors.lastname: Logie
authors.forename: Alan R
authors.initials: AR
authors.lastname: Prescott
authors.forename: Terry G
authors.initials: TG
authors.lastname: Unterman
authors.forename: Jean
authors.initials: J
authors.lastname: Harthill
authors.forename: Graham
authors.initials: G
authors.lastname: Rena
mesh_terms: D021581:Active Transport, Cell Nucleus; D007464:Clioquinol / Q000494:pharmacology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D005943:Gluconeogenesis / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D006912:Hydroxyquinolines / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D015032:Zinc / Q000494:pharmacology
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D006912:Hydroxyquinolines; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D007464:Clioquinol; D051057:Proto-Oncogene Proteins c-akt; D015032:Zinc