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AMPK inhibits MTDH expression via GSK 3β and SIRT 1 activation: potential role in triple negative breast cancer cell proliferation
Author(s) -
Gollavilli Paradesi Naidu,
Kanugula Anantha Koteswararao,
Koyyada Rajeswari,
Karnewar Santosh,
Neeli Praveen Kumar,
Kotamraju Srigiridhar
Publication year - 2015
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13391
Subject(s) - ampk , downregulation and upregulation , cancer research , triple negative breast cancer , chemistry , cell growth , protein kinase a , amp activated protein kinase , phosphorylation , biology , medicine , breast cancer , cancer , biochemistry , gene
Recent studies have highlighted the involvement of metadherin ( MTDH ), an oncogenic protein, in promoting cancer progression, metastasis and chemoresistance in many cancers including mammary carcinomas. However, the molecular regulation of MTDH is still not completely understood. In this study we document that AMP activated protein kinase ( AMPK ) activation‐induced anti‐proliferative effects are, in part, mediated by inhibiting MTDH expression in MDA ‐ MB ‐231 and BT ‐549 triple negative breast cancer ( TNBC ) cells. 5‐Aminoimidazole‐4‐carboxamide ribonucleotide ( AICAR ), an AMPK activator, caused growth arrest, inhibition of migration and invasion of TNBC cells. Intriguingly, AICAR or metformin treatment resulted in significant downregulation of MTDH expression via inhibiting c‐Myc expression. In contrast, treatment of cells with compound C, an inhibitor of AMPK , increased both c‐Myc and MTDH expressions in TNBC cells. Also, AMPK activation caused increased glycogen synthase kinase 3β ( GSK 3β) activity by inhibiting the inactive phosphorylation at Ser9, on the one hand, and activation of sirtuin1 ( SIRT 1) by inhibiting Ser47 phosphorylation, as evidenced by deacetylation of p53, on the other hand. Moreover, AMPK ‐induced GSK 3β and SIRT 1 activities were found to be responsible for inhibiting c‐Myc‐mediated upregulation of MTDH , as LiCl (an inhibitor of GSK 3β) and EX ‐527 (an inhibitor of SIRT 1) reversed AICAR ‐mediated downregulation of c‐Myc and MTDH expressions. Similar results were observed with si SIRT 1 treatment. Furthermore, AICAR and EX ‐527 treatments caused increased cell death under MTDH ‐depleted conditions. Finally, we uncovered a novel regulation of MTDH expression and showed that AMPK activation by inducing GSK 3β and SIRT 1 downregulates MTDH expression via inhibiting c‐Myc in TNBC cells.