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Exendin-4 inhibits the survival and invasiveness of two colorectal cancer cell lines via suppressing GS3Kβ/β-catenin/NF-κB axis through activating SIRT1

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摘要 This study examined if the anti-tumorigenesis effect of Exendin-4 in HT29 and HCT116 colorectal cancer(CRC)involves modulation of SIRT1 and Akt/GSR3K/β-catenin/NF-κB axis.HT29 and HCT116 cells were treated either with increasing levels of Exendin-4(0.0-200μM)or with Exendin-4(at its IC50)in the presence or absence of EX-527(10μM/a selective SIRT1 inhibitor)or Exendin-4(9-39)amide(E(9-39)A)(1μM/an Exendin-4 antagonist).In a dose-dependent manner,Exendin-4 inhibited cell survival,but enhanced levels of lactate dehydrogenase(LDH)and single-stranded DNA(ssDNA)in both HT29 and HCT116.In both cell lines and at it has an IC50(45μM for HT29 and 35μM for HCT1165),Exendin-4 also significantly reduced cell survival,migration,and invasion of both cell types,with no effect on the expression GLP-1 receptors(GLPRs)nor of the activity of Akt.At these doses,Exendin-4 also increased the expression of SIRT1 but reduced the acetylation of NF-κB and the expression of Bax and cleaved caspase-3 and in both cell lines.Concomitantly,protein levels of p-GS3Kβ(Ser9),total and acetylatedβ-catenin,and Anix2 were significantly decreased,but levels of p-GS3Kβ(Ser9)and p-β-catenin(Ser33/37/Thr41)were significantly increased in both HT29 and HCT116-exendin-4 treated cells.All the effects exerted by Exendin-4 were completely prevented by Ex527 or E(9-39)A.In conclusion,Exendin-4 suppresses the tumorigenesis of HT29 and HCT116 CRC cell activation of GS3Kβ-induced inhibition ofβ-catenin and NF-κβin a SIRT1-dependent mechanism.
出处 《BIOCELL》 SCIE 2021年第5期1337-1353,共17页 生物细胞(英文)
基金 the deanship of Scientific Research at King Khalid University,Abha,KSA for supporting this work under grant number(R.G.P.2/80/41) the work was supported by the Taif University Researchers Supporting Project Number(TURSP-2020/99) Taif University,Taif,Saudi Arabia and this work was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University through the Fast-track Research Funding Program.
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