The Influence of Extracellular Citrate in Physiological Concentration on the Proliferation of Malignant Melanoma

Cancer cells rely on citrate for multiple metabolic processes, suggesting that limiting the availability of extracellular citrate may represent a novel therapeutic strategy. The plasma membrane citrate transporter (pmCiC) has been implicated in the pathogenesis of several cancers before, and its activity can be inhibited by gluconate. Tissue samples from patients were stained, and pmCiC expression was analysed and correlated with clinical course. Melanoma cells were treated with or without citrate in physiological concentration and with or without gluconate, a pmCiC inhibitor. Cell proliferation rates were subsequently measured. pmCiC expression was observed in 58.2% of primary melanomas and 76.5% of melanoma metastases, but only in 22.2% of benign nevi. However, pmCiC expression did not correlate with the response to novel melanoma-specific therapies. In the presence of pmCiC, melanoma cells exhibited significantly increased proliferation when exposed to extracellular citrate. This effect was blocked by the addition of gluconate. Extracellular citrate uptake via pmCiC appears to contribute to the pathogenesis of malignant melanoma. Notably, inhibition of pmCiC by gluconate effectively suppressed citrate-induced proliferation.