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

Abstract

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.

Hsp74/14‐3‐3σ Complex Mediates Centrosome Amplification by High Glucose, Insulin, and Palmitic Acid

“…In the present study, we showed that high glucose, insulin, and palmitic acid could induce centrosome amplification (Figure A,B) and 14‐3‐3σ was a signal mediator, which is in agreement with our previous report that the experimental treatment induces centrosome amplification via ROCK1/14‐3‐3σ complex . Moreover, previous report indicated 14‐3‐3 proteins interacted with over 200 human phosphoproteins in HeLa cells using 14‐3‐3 affinity chromatography .…”

“…We have recently reported that the level of centrosome amplification is increased in peripheral blood mononuclear cells from patients with type 2 diabetes. AKT‐ROS‐dependent upregulation of 14‐3‐3σ and ROCk1 as well as their binding and translocation to centrosome is the underlying signal transduction pathway for the diabetes‐associated centrosome amplification . In the present study, we further investigated the molecular basis of centrosome amplification associated with T2DM using colon cancer cells as an experimental model, which were treated with high glucose, insulin, and palmitic acid.…”

“…Palmitic acid, the most common saturated free fatty acid, is often used to investigate the effects of free fatty acids, in particular the adverse effects . We have recently reported that T2DM promotes cell centrosome amplification via AKT‐ROS‐dependent signaling of 14‐3‐3σ and ROCK1, and the pathophysiological factors in T2DM are the triggers. These results implicate that centrosome amplification is a candidate biological link between T2DM and cancer development.…”

Attenuation of doxorubicin-induced cardiotoxicity by cryptotanshinone detected through association analysis of transcriptomic profiling and KEGG pathway

“…14-3-3σ is a member of the 14-3-3 family, and the members of this family are highly conserved acidic proteins widely expressed in tissue cells [23]. 14-3-3σ activation is dependent on AKT-ROS signaling stimulated by the diabetic pathophysiological factors [24]. Meanwhile, in an ischemia-perfusion injury model, increased JNK activation could promote mitochondria-mediated apoptosis through the mitochondrial translocation of proapoptotic proteins dependent on its release from 14-3-3σ [25].…”

Co-Operation between Aneuploidy and Metabolic Changes in Driving Tumorigenesis

“…Exogenous H 2 O 2 also causes centrosome amplification [111], which often results in aneuploidy [112]. Similarly, ROS associated with type 2 diabetes increased the likelihood of centrosome amplification via disruption of centrosomal ROCK1 [113]. ROS has also been reported to disrupt the mitotic machinery, for example, by oxidation of Aurora A and B, increasing the occurrence of misaligned chromosomes and chromatin bridges, resulting in aneuploidy [114,115].…”