The Pathophysiological Factors Of Type 2 Diabetes Induce Centrosome Amplification Via PPAR?-SKA1

Diabetes is the third most chronic non-communicable disease that endangers human health today.Type 2 diabetes accounts for more than 95% of diabetes.Epidemiological research have illustrated patients suffering from type 2 diabetes have a higher risk of developing multiple types of cancers and worsened prognosis,including colon cancer.However,the link between diabetes and cancer remains unknown.Centrosome amplification is common in cancers and is often associated with poor prognosis.Recent findings show that it is sufficient to initiate tumorigenesis and increase the invasion potential of cancer cells.We have found that type 2 diabetes promotes centrosome amplification,and the pathophysiological factors(i.e.,high glucose,insulin and palmitic acid)are the triggers,which suggest that diabetes favors cencer development via induction of cell centrosome amplification.The study aimed to investigate the molecular basis of the diabetes-associated centrosome amplification,which focuses on PPAR? and SKA1.MethodsTreatment of HCT116 cells,MCF-7 cells and Hela cells with high glucose(15m M),free fatty acid(palmitic acid;150 M)and insulin(5n M)were used as experimental models.This treatment was designed to simulate the physiological environment of type 2 diabetes.Centrosomes were visualized using immunofluorescent staining.Western blot analysis was performed to quantify protein levels.si RNA was employed to knock down protein level.ResultsCentrosome amplification was increased in HCT116,MCF-7 and Hela cells after treatment with glucose,insulin and palmitic acid,supporting our previous results that these pathophysiological factors are the triggers for centrosome amplification;HCT116 cells were used for further studies.I found that the treatment increased the protein levels of PPAR? and SKA1,which could be inhibited using si RNA.Moreover,si RNA of PPAR? or SKA1 was able to attenuate the treatment-increased centrosome amplification.The results suggest that PPAR? and SKA1 are signal mediators for the diabetes-associated amplification;This part of study investigated the relationship between PPAR? and SKA1.Knockdown of PPAR? inhibited the treatment-increased protein level of PPAR?,suggesting that PPAR? is upstream of SKA1 in the signaling pathway.Furthermore,chromatin immunoprecipitation analysis demonstrated that PPAR? up-regulates SKA1 expression by directly enhancing its transcription;Finally,I found that the PPAR? agonist rosiglitazone alone could increased the protein levels of PPAR? and SKA1 as well as centrosome amplification.However,in the samples treated with high glucose,insulin and palmitic acid,rosiglitazone did not further increase the expressions of PPAR? and SKA1 as well as centrosome amplification.ConclusionsMy results suggest that PPAR? promotes the diabetes-associated centrosome amplification via enhancing the expression of SKA1 at the transcription level.