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Saxagliptin Induces ?-Cell Proliferation through Increasing Stromal Cell-Derived Factor-1? In Vivo and In Vitro.

ABSTRACT: Dipeptidyl peptidase-4 inhibitors, such as saxagliptin, have been reported to have beneficial effects on ?-cell function, but the specific underlying mechanism remains unclear. Stromal cell-derived factor-1? (SDF-1?), a chemokine produced in multiple organs, has been considered as a crucial regulator in promoting ?-cell survival. Here, we speculate that SDF-1? might mediate the effect of saxagliptin on improving ?-cell function. After 12-week saxagliptin treatment in high-fat diet/streptozotocin-induced diabetic rats, significant improvement in pancreas insulin secretion capacity evaluated by hyperglycemia clamp and increased ?-cell to ?-cell areas ratio were observed. Saxagliptin significantly induced ?-cell proliferation and upregulated the expression of proliferation-related factors including c-myc and cyclind D1 determined with western blotting from the isolated islets. The expression/activity of DPP-4 was significantly reduced and paralleled with the restoration of SDF-1? levels in the saxagliptin-treated diabetic rats, subsequently the key WNT-signaling regulators, ?-catenin, and AKT were activated. However, the effect of saxagliptin inducing ?-cell proliferation was attenuated when we silenced the SDF-1? receptor (CXCR4) with RNAi in INS cell lines. Collectively, our data indicate that SDF-1? mediates the protective effect of saxagliptin on ?-cell proliferation, suggesting that DPP-4 inhibitors have the potential role on delaying ?-cell failure and SDF-1? could be a therapeutic target of ?-cell regeneration.

SUBMITTER: Li CJ

PROVIDER: S-EPMC5711777 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

Saxagliptin Induces β-Cell Proliferation through Increasing Stromal Cell-Derived Factor-1α <i>In Vivo</i> and <i>In Vitro</i>.

Li Chun-Jun CJ Sun Bei B Fang Qian-Hua QH Ding Min M Xing Yun-Zhi YZ Chen Li-Ming LM Yu De-Min DM

Frontiers in endocrinology 20171127

Dipeptidyl peptidase-4 inhibitors, such as saxagliptin, have been reported to have beneficial effects on β-cell function, but the specific underlying mechanism remains unclear. Stromal cell-derived factor-1α (SDF-1α), a chemokine produced in multiple organs, has been considered as a crucial regulator in promoting β-cell survival. Here, we speculate that SDF-1α might mediate the effect of saxagliptin on improving β-cell function. After 12-week saxagliptin treatment in high-fat diet/streptozotocin ...[more]

PMID: 29230196

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Project description:Purpose: Recent studies indicate that pregnancy upregulated non-ubiquitous calmodulin kinase (PNCK) is significantly up-regulated in breast and renal carcinomas. However, the expression profile and its biological relevance of PNCK in nasopharyngeal carcinoma (NPC) have not been elucidated. Methods: The expression level of PNCK was detected in specimens of NPC (n=10) and normal tissues (n=10) by real-time PCR and immunohistochemistry. Celigo Cell Counting and MTT assay were used to measure cell viability. Apoptosis was detected by flow cytometric analysis and caspases 3/7 activity assay. Real-time PCR and Western blotting were performed to evaluate the expression of PNCK. The bioluminescence imaging was used to evaluate the effects of PNCK knockdown on tumor growth using a xenograft animal model. The global gene expression profile was determined in wild type and PNCK-depleted CNE-2 cells via transcriptomics analysis. For mechanical investigation, the changes of PI3K/AKT/mTOR signaling pathway were detected by Western blotting. Results: The mRNA and protein levels of PNCK were increased in human NPC samples. In vitro experiments showed that shRNA or CRISPR-Cas9 mediated silencing of PNCK inhibited proliferation and induced apoptosis in NPC cells. In addition, in vivo assay revealed that knockdown of PNCK suppressed tumor growth. Consistently, a significant reduction of tumor bioluminescence in mice inoculated with PNCK-knockdown cells compared to that of control cells. In gene expression, the transcriptomics analysis revealed that there were 589 upregulated genes and 589 downregulated genes in PNCK-knockdown cells. Ingenuity Pathway Analysis (IPA) identified significant changes of PI3K/AKT/mTOR signaling pathway in PNCK-knockdown cells. Furthermore, western blot analysis revealed that interference with PNCK reduced the phosphorylation levels of PI3K, AKT and mTOR in CNE-2 cells. Conclusion: This study for the first time demonstrates that knockdown of PNCK could suppress growth and induce apoptosis of NPC cells both in vitro and in vivo by regulating PI3K/AKT/mTOR signaling pathway. These findings suggest that PNCK might be a novel therapeutic target for NPC treatment.

Dataset Information

Saxagliptin Induces ?-Cell Proliferation through Increasing Stromal Cell-Derived Factor-1? In Vivo and In Vitro.

Publications

Saxagliptin Induces β-Cell Proliferation through Increasing Stromal Cell-Derived Factor-1α <i>In Vivo</i> and <i>In Vitro</i>.

Similar Datasets

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