title: Metformin increases antitumor activity of MEK inhibitors through GLI1 downregulation in LKB1 positive human NSCLC cancer cells.
abstract: OBJECTIVE
  Metformin, widely used as antidiabetic drug, showed antitumoral effects expecially in combination with chemotherapy. Our group recently has demonstrated that metformin and gefitinib are synergistic in LKB1-wild-type NSCLC cells. In these models, metformin as single agent induced an activation and phosphorylation of mitogen-activated-protein-kinase (MAPK) through an increased C-RAF/B-RAF heterodimerization.
  
  
  METHODS
  Since single agent metformin enhances proliferating signals through the RAS/RAF/MAPK pathway, and several MEK inhibitors (MEK-I) demonstrated clinical efficacy in combination with other agents in NSCLC, we tested the effects of metformin plus MEK-I (selumetinib or pimasertib) on proliferation, invasiveness, migration abilities in vitro and in vivo in LKB1 positive NSCLC models harboring KRAS wild type and mutated gene.
  
  
  RESULTS
  The combination of metformin with MEK-I showed a strong anti-proliferative and proapoptotic effect in Calu-3, H1299, H358 and H1975 human NSCLC cell lines, independently from the KRAS mutational status. The combination reduced the metastatic behaviour of NSCLC cells, via a downregulation of GLI1 trascritional activity, thus affecting the transition from an epithelial to a mesenchymal phenotype. Metformin and MEK-Is combinations also decreased the production and activity of MMP-2 and MMP-9 by reducing the NF-jB (p65) binding to MMP-2 and MMP-9 promoters.
  
  
  CONCLUSIONS
  Metformin potentiates the antitumor activity of MEK-Is in human LKB1-wild-type NSCLC cell lines, independently from the KRAS mutational status, through GLI1 downregulation and by reducing the NF-jB (p65)-mediated transcription of MMP-2 and MMP-9.
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara", Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Carminia Maria
authors.initials: CM
authors.lastname: Della Corte
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara", Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Ciaramella
authors.affiliation: Oncologia Medica, Dipartimento di Medicina Clinica e Chirurgia, Università degli studi di Napoli "Federico II", Naples, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Di Mauro
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Istituto di Endocrinologia ed Oncologia Sperimentale "G. Salvatore" (IEOS), University of Naples "Federico II", Naples, Italy.
authors.forename: Maria Domenica
authors.initials: MD
authors.lastname: Castellone
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara", Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Papaccio
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara", Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Morena
authors.initials: M
authors.lastname: Fasano
authors.affiliation: Medicina Interna, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara", Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Ferdinando Carlo
authors.initials: FC
authors.lastname: Sasso
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara", Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Martinelli
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara", Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Troiani
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara", Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: De Vita
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara", Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Orditura
authors.affiliation: Oncologia Medica, Dipartimento di Medicina Clinica e Chirurgia, Università degli studi di Napoli "Federico II", Naples, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bianco
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara", Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara", Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Floriana
authors.initials: F
authors.lastname: Morgillo
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000071676:Zinc Finger Protein GLI1
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; C400551:GLI1 protein, human; D007004:Hypoglycemic Agents; C550600:N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D009536:Niacinamide; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D048369:MAP Kinase Kinase 1
keywords: MEK; NSCLC; metformin; pimasertib; selumetinib