AMPK inhibits MTDH expression via GSK3β and SIRT1 activation: potential role in triple negative breast cancer cell proliferation

摘要: Recent studies have highlighted the involvement of metadherin (MTDH), an oncogenic protein, in promoting cancer progression, metastasis and chemoresistance many cancers including mammary carcinomas. However, molecular regulation MTDH is still not completely understood. In this study we document that AMP activated protein kinase (AMPK) activation-induced anti-proliferative effects are, part, mediated by inhibiting expression MDA-MB-231 BT-549 triple negative breast (TNBC) cells. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR), AMPK activator, caused growth arrest, inhibition migration invasion TNBC Intriguingly, AICAR or metformin treatment resulted significant downregulation via c-Myc expression. contrast, cells with compound C, inhibitor AMPK, increased both expressions Also, activation glycogen synthase 3β (GSK3β) activity inactive phosphorylation at Ser9, on one hand, sirtuin1 (SIRT1) Ser47 phosphorylation, as evidenced deacetylation p53, other hand. Moreover, AMPK-induced GSK3β SIRT1 activities were found to be responsible for c-Myc-mediated upregulation MTDH, LiCl (an GSK3β) EX-527 SIRT1) reversed AICAR-mediated expressions. Similar results observed siSIRT1 treatment. Furthermore, treatments cell death under MTDH-depleted conditions. Finally, uncovered a novel showed inducing downregulates