Metformin inhibits age-related centrosome amplification in Drosophila midgut stem cells through AKT/TOR pathway

Na, Hyun Jin; Park, Joung Sun; Pyo, Jung-Hoon; Jeon, Ho Jun; Kim, Young S.; Arking, Robert; Yoo, Mi‐Ae

doi:10.1016/j.mad.2015.05.004

Cited by 36 publications

(21 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3-3-6) support the findings that AKT [23] and ROS [17] can mediate centrosome amplification, and further place AKT upstream of ROS. In an apoptosis model, activation of ROCK1 causes AKT inactivation [24], which is different from our results that placed ROCK1 downstream of AKT activation (Figs.…”

Section: Discussionsupporting

confidence: 64%

Type 2 Diabetes Promotes Cell Centrosome Amplification via AKT-ROS-Dependent Signalling of ROCK1 and 14-3-3σ

Wang¹,

Lü²,

Wang³

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Type 2 diabetes is associated with oxidative stress and DNA damage which can cause centrosome amplification. Thus, the study investigated centrosome amplification in type 2 diabetes and the underlying mechanisms. Methods: Centrosome numbers in human peripheral blood mononuclear blood cells (PBMC) from healthy subjects and patients with type 2 diabetes were compared to access the association between type 2 diabetes and centrosome amplification. Colon cancer cells were used to investigate the molecular mechanisms underlying the centrosome amplification triggered by high glucose, insulin and palmitic acid. Western blot analysis was used to quantify the level of protein and protein phosphorylation. Immunofluorescent staining was performed to detect centrosomes. ROS was quantified using flow cytometry technique. Transcriptpmic profiling was performed using Illumina HiSeq^TM500 platform. Results: We found that centrosome amplification was increased PBMC from the type 2 diabetic patients, which correlated with the levels of fasting blood glucose and HbA1c. High glucose, insulin and palmitic acid, alone or in combinations, induced ROS production and centrosome amplification. Together, they increased AKT activation as well as the expression, binding and centrosome translation of ROCK1 and 14-3-3σ. Results from further analyses showed that AKT-ROS-dependent upregulations of expression, binding and centrosome translocation of ROCK1 and 14-3-3σ was the molecular pathway underlying the centrosome amplification in vitro triggered by high glucose, insulin and palmitic acid. Moreover, the key in vitro molecular signalling events activated by high glucose, insulin and palmitic acid were verified in PBMC from the patients with type 2 diabetes. Conclusion: Our results show that type 2 diabetes promotes cell centrosome amplification, and suggest that the diabetic pathophysiological factors-activated AKT-ROS-dependent signalling of ROCK1 and 14-3-3σ is the underlying molecular mechanism.

show abstract

Section: Discussionsupporting

confidence: 64%

Type 2 Diabetes Promotes Cell Centrosome Amplification via AKT-ROS-Dependent Signalling of ROCK1 and 14-3-3σ

Wang¹,

Lü²,

Wang³

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…Our results (Figs. 3-6) support the findings that AKT (Na et al, 2015) and ROS (Chae et al, 2005) can mediate centrosome amplification, and further place AKT upstream of ROS. In an apoptosis model, activation of ROCK1 causes AKT inactivation (Zhang et al, 2016), which is different from our results that placed ROCK1 downstream of AKT activation (Figs.…”

Section: Discussionsupporting

confidence: 57%

Type 2 diabetes promotes cell centrosome amplification and the role of AKT-ROS-dependent signalling of ROCK1 and 14-3-3σ

Wang

Lü

Wang

et al. 2017

Preprint

View full text Add to dashboard Cite

show abstract

“…35 Fourth, metformin inhibits the AKT/TOR signalling pathway to inhibit age-and oxidative stress-induced centrosome amplification. 36 Here we found that the improvements in cardiac remodelling caused by metformin upon β-AR over-activation in the old mice are due to AMPK activation and a decrease in β-arrestin 1 expression ( Fig. 5).…”

Section: Discussionmentioning

confidence: 64%

Exacerbated cardiac fibrosis induced by β‐adrenergic activation in old mice due to decreased AMPK activity

Wang

Song

et al. 2016

Clin Exp Pharma Physio

View full text Add to dashboard Cite

Senescent hearts exhibit defective responses to β-adrenergic receptor (β-AR) over-activation upon stress, leading to more severe pathological cardiac remodelling. However, the underlying mechanisms remain unclear. Here, we investigated the role of adenosine monophosphate-activated protein kinase (AMPK) in protecting against ageing-associated cardiac remodelling in mice upon β-AR over-activation. 10-week-old (young) and 18-month-old (old) mice were subcutaneously injected with the β-AR agonist isoproterenol (ISO; 5 mg/kg). More extensive cardiac fibrosis was found in old mice upon ISO exposure than in young mice. Meanwhile, ISO treatment decreased AMPK activity and increased β-arrestin 1, but not β-arrestin 2, expression, and the effects of ISO on AMPK and β-arrestin 1 were greater in old mice than in young mice. Similarly, young AMPKα2-knockout (KO) mice showed more extensive cardiac fibrosis upon ISO exposure than that was observed in age-matched wild-type (WT) littermates. The extent of cardiac fibrosis in WT old mice was similar to that in young KO mice. Additionally, AMPK activities were decreased and β-arrestin 1 expression increased in KO mice. In contrast, the AMPK activator metformin decreased β-arrestin 1 expression and attenuated cardiac fibrosis in both young and old mice upon ISO exposure. In conclusion, more severe cardiac fibrosis is induced by ISO in old mice than in young mice. A decrease in AMPK activity, which further increases β-arrestin 1 expression, is the central mechanism underlying the ageing-related cardiac fibrosis induced by ISO. The AMPK activator metformin is a promising therapeutic agent for treating ageing-related cardiac remodelling upon β-AR over-activation.

show abstract

Metformin inhibits age-related centrosome amplification in Drosophila midgut stem cells through AKT/TOR pathway

Cited by 36 publications

References 77 publications

Type 2 Diabetes Promotes Cell Centrosome Amplification via AKT-ROS-Dependent Signalling of ROCK1 and 14-3-3σ

Type 2 Diabetes Promotes Cell Centrosome Amplification via AKT-ROS-Dependent Signalling of ROCK1 and 14-3-3σ

Type 2 diabetes promotes cell centrosome amplification and the role of AKT-ROS-dependent signalling of ROCK1 and 14-3-3σ

Exacerbated cardiac fibrosis induced by β‐adrenergic activation in old mice due to decreased AMPK activity

Contact Info

Product

Resources

About