Abstract
Intrinsic or acquired drug resistance is one of the major problems compromising the success of antineoplastic treatments. Several evidences correlated some therapeutic failures with changes in cell metabolic asset and in line with these findings, hindering the glycolytic metabolism of cancer cells via lactate dehydrogenase (LDH) inhibition was found to overcome the resistance to chemotherapeutic agents. Lactate, the product of LDH reaction, was shown to be involved in epigenetic regulation of gene expression. The experiments described in this paper were aimed at highlighting a possible direct effect of lactate in modifying the response of cancer cells to a chemotherapeutic treatment. To discriminate between the effects potentially caused by glycolytic metabolism from those directly referable to lactate, we selected cancer cell lines able to grow in glucose deprived conditions and evaluated the impact of lactate on the cellular response to cisplatin-induced DNA damage. In lactate-exposed cells we observed a reduced efficacy of cisplatin, which was associated with reduced signatures of DNA damage, enhanced DNA recombination competence and increased expression of a panel of genes involved in DNA repair. The identified genes take part in mismatch and nucleotide excision repair pathways, which were found to contribute in restoring the cisplatin-induced DNA damage. The obtained results suggest that this metabolite could play a role in reducing the efficacy of antineoplastic treatments.
Highlights
IntroductionThe activated glucose metabolism of cancer cells is functional in coping with their increased energy demand and need of metabolic intermediates, required to build-up new macromolecules [1,2]
The activated glucose metabolism of cancer cells is functional in coping with their increased energy demand and need of metabolic intermediates, required to build-up new macromolecules [1,2]. the discovery of this metabolic feature dates back to almost one century ago [3], it is only in recent years that evidences showing a direct correlation between enhanced glycolysis and changes in gene expression have been obtained
In order to evidence a direct contribute of lactate in this phenomenon, we searched human cancer cell lines able to grow in glucose deprived conditions (L-15 medium)
Summary
The activated glucose metabolism of cancer cells is functional in coping with their increased energy demand and need of metabolic intermediates, required to build-up new macromolecules [1,2]. The discovery of this metabolic feature dates back to almost one century ago [3], it is only in recent years that evidences showing a direct correlation between enhanced glycolysis and changes in gene expression have been obtained. The metabolic reprogramming of cancer cells was found to impact on distinct morphological features of cancer cell nucleus [4]. Metabolites originating during the glycolytic cascade have been shown to increase histone acetylation and promote an open chromatin structure [4,5], which facilitates the transcriptional and replication machineries triggered by oncogenes activation. Elevation of glycolysis seems to confer cancer cells resistance to ionizing radiation [6], while its inhibition results in compromised DNA repair [7]
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