Lactate Induces Cisplatin Resistance in S. cerevisiae through a Rad4p-Dependent Process

Abstract

Cisplatin is a widely used antineoplastic agent that has DNA as the main target, though cellular resistance hampers its therapeutic efficacy. An emerging hallmark of cancer cells is their altered metabolism, characterized by increased glycolysis even under aerobic conditions, with increased lactate production (known as the Warburg effect). Although this altered metabolism often results in increased resistance to chemotherapy, it also provides an opportunity for targeted therapeutic intervention. It has been suggested that cisplatin cytotoxicity can be affected by tumor metabolism, though with varying effects. We therefore sought to better characterize how lactate affects cisplatin sensitivity in the simplified Saccharomyces cerevisiae model. We show that lactate renders yeast cells resistant to cisplatin, independently of growth rate or respiration ability. We further show that histone acetylation is not affected, but histone phosphorylation is decreased in lactate-containing media. Finally, we show that Rad4p, essential for nucleotide excision repair, is required for the observed phenotype and thus likely underlies the mechanism responsible for lactate-mediated resistance to cisplatin. Overall, understanding how lactate modulates cisplatin sensitivity will aid in the development of new strategies to overcome drug resistance.

Hypoxia induced lactate acidosis modulates tumor microenvironment and lipid reprogramming to sustain the cancer cell survival

“…After 180 min of exposure to the respective treatments, they observed a reduced sensitivity to cisplatin in the presence of lactate. Furthermore, western blotting results showed higher phosphorylation of Rad4p in lactate medium-cultured cells, although no change in histone acetylation was observed ( 89 ). It is previously reported that Rad4p (a DNA repairing protein that belongs to xeroderma pigmentosum family) has important role in nucleotide excision repair ( 90 ).…”