title: AMPK inhibits MTDH expression via GSK3β and SIRT1 activation: potential role in triple negative breast cancer cell proliferation.
abstract: 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 (GSK3β) activity by inhibiting the inactive phosphorylation at Ser9, on the one hand, and activation of sirtuin1 (SIRT1) by inhibiting Ser47 phosphorylation, as evidenced by deacetylation of p53, on the other hand. Moreover, AMPK-induced GSK3β and SIRT1 activities were found to be responsible for inhibiting c-Myc-mediated upregulation of MTDH, as LiCl (an inhibitor of GSK3β) and EX-527 (an inhibitor of SIRT1) reversed AICAR-mediated downregulation of c-Myc and MTDH expressions. Similar results were observed with siSIRT1 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 GSK3β and SIRT1 downregulates MTDH expression via inhibiting c-Myc in TNBC cells.
authors.affiliation: Centre for Chemical Biology, CSIR Indian Institute of Chemical Technology, Hyderabad, India.|Academy of Scientific and Innovative Research, Training and Development Complex, Chennai, India.
authors.forename: Paradesi Naidu
authors.initials: PN
authors.lastname: Gollavilli
authors.affiliation: Centre for Chemical Biology, CSIR Indian Institute of Chemical Technology, Hyderabad, India.
authors.forename: Anantha Koteswararao
authors.initials: AK
authors.lastname: Kanugula
authors.affiliation: Centre for Chemical Biology, CSIR Indian Institute of Chemical Technology, Hyderabad, India.
authors.forename: Rajeswari
authors.initials: R
authors.lastname: Koyyada
authors.affiliation: Centre for Chemical Biology, CSIR Indian Institute of Chemical Technology, Hyderabad, India.|Academy of Scientific and Innovative Research, Training and Development Complex, Chennai, India.
authors.forename: Santosh
authors.initials: S
authors.lastname: Karnewar
authors.affiliation: Centre for Chemical Biology, CSIR Indian Institute of Chemical Technology, Hyderabad, India.
authors.forename: Praveen Kumar
authors.initials: PK
authors.lastname: Neeli
authors.affiliation: Centre for Chemical Biology, CSIR Indian Institute of Chemical Technology, Hyderabad, India.|Academy of Scientific and Innovative Research, Training and Development Complex, Chennai, India.
authors.forename: Srigiridhar
authors.initials: S
authors.lastname: Kotamraju
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008565:Membrane Proteins; D009363:Neoplasm Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D034622:RNA Interference; D016601:RNA-Binding Proteins; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; C483039:MTDH protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: AMPK; SIRT1; breast cancer; metadherin; tumour promotion and progression