Exploring metabolic reprogramming in melanoma via acquired resistance to the oxidative phosphorylation inhibitor...

Area of Science:

• Oncology
• Cancer Metabolism
• Melanoma Research

Background:

• Therapeutic failure in cancer is linked to metabolic plasticity.
• Metabolic modulators show promise, but underlying molecular events are unclear.

Purpose of the Study:

• To investigate melanoma cell adaptation to prolonged oxidative phosphorylation inhibition by phenformin.
• To characterize the molecular and functional changes during this metabolic switch.

Main Methods:

• Melanoma cells were cultured with high-dose phenformin for 3 months (R-cells).
• Phenotypic analysis (viability, migration, invasion) and microarray analysis were performed.
• Oxygen consumption and extracellular acidification rates were measured.
• R-cells were treated with vemurafenib, and phenformin was withdrawn.

Main Results:

• Phenformin-treated R-cells showed reduced viability, migration, and invasion compared to parental S-cells.
• Microarray analysis revealed an energy production strategy switch and modulation of immunological genes.
• R-cells exhibited decreased oxygen consumption and increased extracellular acidification rates.
• Vemurafenib treatment reduced R-cell viability, growth, and ERK activation.
• Phenformin withdrawal reversed the R-cell phenotype.

Conclusions:

• Prolonged phenformin treatment induces a reversible metabolic switch in melanoma cells.
• This adaptation involves significant changes in energy metabolism and gene expression.
• The study provides an in vitro model for metabolic reprogramming in melanoma.