title: Metformin inhibits growth and enhances radiation response of non-small cell lung cancer (NSCLC) through ATM and AMPK.
abstract: BACKGROUND
  We examined the potential of metformin (MET) to enhance non-small cell lung cancer (NSCLC) responses to ionising radiation (IR).
  
  
  METHODS
  Human NSCLC cells, mouse embryonic fibroblasts from wild-type and AMP-activated kinase (AMPK) α1/2-subunit(-/-) embryos (AMPKα1/2(-/-)-MEFs) and NSCLC tumours grafted into Balb/c-nude mice were treated with IR and MET and subjected to proliferation, clonogenic, immunoblotting, cell cycle and apoptosis assays and immunohistochemistry (IHC).
  
  
  RESULTS
  Metformin (2.5 μM-5 mM) inhibited proliferation and radio-sensitised NSCLC cells. Metformin (i) activated the ataxia telengiectasia-mutated (ATM)-AMPK-p53/p21(cip1) and inhibited the Akt-mammalian target of rapamycin (mTOR)-eIF4E-binding protein 1 (4EBP1) pathways, (ii) induced G1 cycle arrest and (iii) enhanced apoptosis. ATM inhibition blocked MET and IR activation of AMPK. Non-small cell lung cancer cells with inhibited AMPK and AMPKα1/2(-/-)-MEFs were resistant to the antiproliferative effects of MET and IR. Metformin or IR inhibited xenograft growth and combined treatment enhanced it further than each treatment alone. Ionising radiation and MET induced (i) sustained activation of ATM-AMPK-p53/p21(cip1) and inhibition of Akt-mTOR-4EBP1 pathways in tumours, (ii) reduced expression of angiogenesis and (iii) enhanced expression of apoptosis markers.
  
  
  CONCLUSIONS
  Clinically achievable MET doses inhibit NSCLC cell and tumour growth and sensitise them to IR. Metformin and IR mediate their action through an ATM-AMPK-dependent pathway. Our results suggest that MET can be a clinically useful adjunct to radiotherapy in NSCLC.
authors: Department of Research, Juravinski Cancer Center, 699 Concession Street, Hamilton L8V 5C2, ON, Canada.
authors: Y
authors: Y
authors: Storozhuk
authors: S N
authors: SN
authors: Hopmans
authors: T
authors: T
authors: Sanli
authors: C
authors: C
authors: Barron
authors: E
authors: E
authors: Tsiani
authors: J-C
authors: JC
authors: Cutz
authors: G
authors: G
authors: Pond
authors: J
authors: J
authors: Wright
authors: G
authors: G
authors: Singh
authors: T
authors: T
authors: Tsakiridis
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects; D004622:Embryo, Mammalian; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology / Q000627:therapeutic use*; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011838:Radiation-Sensitizing Agents; D025521:Tumor Suppressor Proteins; D008687:Metformin; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D000263:Adenylate Kinase
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