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

## TL;DR

Extracellular citrate promotes melanoma cell growth through a transporter called pmCiC, and blocking this transporter with gluconate can stop this growth.

## Contribution

The study shows that extracellular citrate supports melanoma proliferation via pmCiC and that gluconate can inhibit this process.

## Key findings

- pmCiC was expressed in 58.2% of primary melanomas and 76.5% of metastases, but only 22.2% of benign nevi.
- Melanoma cells with pmCiC showed increased proliferation when exposed to citrate, which was blocked by gluconate.
- Extracellular citrate uptake via pmCiC contributes to melanoma pathogenesis, and its inhibition suppresses citrate-induced proliferation.

## Abstract

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.