title: Metformin increases PDH and suppresses HIF-1α under hypoxic conditions and induces cell death in oral squamous cell carcinoma.
abstract: BACKGROUND
  Metformin is a biguanide, belonging to the oral hypoglycemic agents and is a widely used in the treatment of type 2 diabetes. Evidence indicate that Metformin inhibits cell proliferation in several human cancers and inhibits the Warburg phenomenon in tumor cells.
  
  
  RESULTS
  Low PDH levels were observed in OSCC, and Metformin promotes an increase in PDH levels in hypoxic conditions. Metformin also reduced HIF-1α mRNA and protein levels. Metformin demonstrated antiproliferative effects, inhibited migration, increased the number of apoptotic cells and increased the transcription of caspase 3.
  
  
  OBJECTIVE
  The present study aims to explore the effects of Metformin in hypoxic conditions. Specifically, we focused on pyruvate dehydrogenase (PDH), (hypoxia-inducible factor 1α) HIF-1α levels and the oral squamous cell carcinoma (OSCC) cell phenotype. Additionally, we also investigated a theoretical consequence of Metformin treatment.
  
  
  METHODS
  PDH levels in patients with OSCC and oral dysplasia were evaluated. Metformin was administered in vitro to test the effect of Metformin under hypoxic conditions. The results were complemented by Bioinformatics analyses.
  
  
  CONCLUSIONS
  In conclusion, our current findings show that Metformin reduces HIF-1α gene expression and increases PDH expression. Metformin inhibits cell proliferation and migration in the OSCC cell line model. Additionally, Metformin enhances the number of apoptotic cells and caspase 3 levels. Interestingly enough, Metformin did not increase the mutant p53 levels under hypoxic conditions.
authors.affiliation: Department of Dentistry, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil.
authors.forename: Talita Antunes
authors.initials: TA
authors.lastname: Guimarães
authors.affiliation: Department of Dentistry, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil.
authors.forename: Lucyana Conceição
authors.initials: LC
authors.lastname: Farias
authors.affiliation: Department of Dentistry, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil.|Instituto Federal de Educação, Ciência e Tecnologia do Norte de Minas Gerais (IFNMG), Araçuaí, Minas Gerais, Brazil.
authors.forename: Eliane Sobrinho
authors.initials: ES
authors.lastname: Santos
authors.affiliation: Faculdades Integradas Pitágoras, Montes Claros, Minas Gerais, Brazil.|Faculdades Unidas do Norte de Minas, Montes Claros, Minas Gerais, Brazil.
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: de Carvalho Fraga
authors.affiliation: Department of Clinical, Surgery and Oral Pathology, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Lissur Azevedo
authors.initials: LA
authors.lastname: Orsini
authors.affiliation: Department of Dentistry, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil.
authors.forename: Leandro
authors.initials: L
authors.lastname: de Freitas Teles
authors.affiliation: Texas Tech University Health Science Center, Lubbock, TX, USA.
authors.forename: John David
authors.initials: JD
authors.lastname: Feltenberger
authors.affiliation: Department of Dentistry, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil.
authors.forename: Sabrin Ferreira
authors.initials: SF
authors.lastname: de Jesus
authors.affiliation: Department of Dentistry, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil.
authors.forename: Marcela Gonçalves
authors.initials: MG
authors.lastname: de Souza
authors.affiliation: Institute of Agricultural Sciences, Food Engineering College, Universidade Federal de Minas Gerais (UFMG), Montes Claros, Minas Gerais, Brazil.
authors.forename: Sérgio Henrique Sousa
authors.initials: SH
authors.lastname: Santos
authors.affiliation: Department of Dentistry, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil.
authors.forename: Alfredo Maurício Batista
authors.initials: AM
authors.lastname: de Paula
authors.affiliation: Department of Clinical, Surgery and Oral Pathology, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Ricardo Santiago
authors.initials: RS
authors.lastname: Gomez
authors.affiliation: Department of Dentistry, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil.
authors.forename: André Luiz Sena
authors.initials: AL
authors.lastname: Guimarães
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D015687:Cell Hypoxia; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D009062:Mouth Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011768:Pyruvate Dehydrogenase Complex; D008687:Metformin
keywords: LDH-A; Metformin; PDH; oral cancer; proliferation