Metformin increases PDH and suppresses HIF-1α under hypoxic conditions and induces cell death in oral squamous cell carcinoma
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Talita Antunes Guimarães1, Lucyana Conceição Farias1, Eliane Sobrinho Santos1,5, Carlos Alberto de Carvalho Fraga6,7, Lissur Azevedo Orsini2, Leandro de Freitas Teles1, John David Feltenberger3, Sabrina Ferreira de Jesus1, Marcela Gonçalves de Souza1, Sérgio Henrique Sousa Santos4, Alfredo Maurício Batista de Paula1, Ricardo Santiago Gomez2,* André Luiz Sena Guimarães1,*
1Department of Dentistry, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil
2Department of Clinical, Surgery and Oral Pathology, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
3Texas Tech University Health Science Center, Lubbock, TX, USA
4Institute of Agricultural Sciences, Food Engineering College, Universidade Federal de Minas Gerais (UFMG), Montes Claros, Minas Gerais, Brazil
5Instituto Federal de Educação, Ciência e Tecnologia do Norte de Minas Gerais (IFNMG), Araçuaí, Minas Gerais, Brazil
6Faculdades Integradas Pitágoras, Montes Claros, Minas Gerais, Brazil
7Faculdades Unidas do Norte de Minas, Montes Claros, Minas Gerais, Brazil
*These authors contributed equally to this work
André Luiz Sena Guimarães, email: [email protected]
Ricardo Santiago Gomez, email: [email protected]
Keywords: proliferation, oral cancer, metformin, PDH, LDH-A
Received: March 21, 2016 Accepted: July 09, 2016 Published: July 26, 2016
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.
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