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2016 ; 15
(14
): 1908-18
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Metformin is also effective on lactic acidosis-exposed melanoma cells switched to
oxidative phosphorylation
#MMPMID27266957
Peppicelli S
; Toti A
; Giannoni E
; Bianchini F
; Margheri F
; Del Rosso M
; Calorini L
Cell Cycle
2016[Jul]; 15
(14
): 1908-18
PMID27266957
show ga
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.