Metformin is also effective on lactic acidosis-exposed melanoma cells switched to oxidative phosphorylation.
Low extracellular pH promotes in melanoma cells a malignant phenotype characterized by an epithelial-to-mesenchymal transition (EMT) program, endowed with mesenchymal markers, high invasiveness and pro-metastatic property. Here, we demonstrate that melanoma cells exposed to an acidic extracellular microenvironment, 6.7±0.1, shift to an oxidative phosphorylation (Oxphos) metabolism. Metformin, a biguanide commonly used for type 2 diabetes, inhibited the most relevant features of acid-induced phenotype, including EMT and Oxphos. When we tested effects of lactic acidosis, to verify whether sodium lactate might have additional effects on acidic melanoma cells, we found that EMT and Oxphos also characterized lactic acid-treated cells. An increased level of motility was the only gained property of lactic acidic-exposed melanoma cells. Metformin treatment inhibited both EMT markers and Oxphos and, when its concentration raised to 10 mM, it induced a striking inhibition of proliferation and colony formation of acidic melanoma cells, both grown in protons enriched medium or lactic acidosis. Thus, our study provides the first evidence that metformin may target either proton or lactic acidosis-exposed melanoma cells inhibiting EMT and Oxphox metabolism. These findings disclose a new potential rationale of metformin addition to advanced melanoma therapy, e.g. targeting acidic cell subpopulation.
a Department of Experimental and Clinical Biomedical Sciences , University of Florence, Istituto Toscano Tumori and Center of Excellence for Research, Transfer and High Education DenoTHE , Florence , Italy.
Silvia
S
Peppicelli
a Department of Experimental and Clinical Biomedical Sciences , University of Florence, Istituto Toscano Tumori and Center of Excellence for Research, Transfer and High Education DenoTHE , Florence , Italy.
Alessandra
A
Toti
a Department of Experimental and Clinical Biomedical Sciences , University of Florence, Istituto Toscano Tumori and Center of Excellence for Research, Transfer and High Education DenoTHE , Florence , Italy.
Elisa
E
Giannoni
a Department of Experimental and Clinical Biomedical Sciences , University of Florence, Istituto Toscano Tumori and Center of Excellence for Research, Transfer and High Education DenoTHE , Florence , Italy.
Francesca
F
Bianchini
a Department of Experimental and Clinical Biomedical Sciences , University of Florence, Istituto Toscano Tumori and Center of Excellence for Research, Transfer and High Education DenoTHE , Florence , Italy.
Francesca
F
Margheri
a Department of Experimental and Clinical Biomedical Sciences , University of Florence, Istituto Toscano Tumori and Center of Excellence for Research, Transfer and High Education DenoTHE , Florence , Italy.
Mario
M
Del Rosso
a Department of Experimental and Clinical Biomedical Sciences , University of Florence, Istituto Toscano Tumori and Center of Excellence for Research, Transfer and High Education DenoTHE , Florence , Italy.
Lido
L
Calorini
D000140:Acidosis, Lactic / Q000473:pathology*; D000222:Adaptation, Physiological / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003373:Coumaric Acids / Q000494:pharmacology; D003470:Culture Media; D006801:Humans; D007773:Lactates / Q000378:metabolism / Q000494:pharmacology; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology*; D008648:Mesoderm / Q000187:drug effects / Q000378:metabolism; D055432:Metabolomics; D008687:Metformin / Q000494:pharmacology*; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010641:Phenotype; D014410:Tumor Stem Cell Assay
D003373:Coumaric Acids; D003470:Culture Media; D007773:Lactates; C007175:alpha-cyano-4-hydroxycinnamate; D008687:Metformin
Acidic microenvironment; cell metabolism; lactic acidosis; melanoma cells; metformin