A Metabolites’ Interplay Can Modulate DNA Repair by Homologous Recombination

Small molecules either derived from cell metabolic reactions or produced by gut bacterial flora have shown the potential of affecting gene expression, which suggests the possibility of interactions able to modulate cellular functions. In this context, the reported experi-ments were aimed at verifying a possible interplay between lactate and butyrate in modu-lating the efficacy of antineoplastic drugs. Butyrate is a product of gut bacterial flora, shown to be endowed with anticancer properties; conversely, increased lactate levels in cancer cells were found to be associated with higher proliferation and drug resistance. For the reported experiments, we adopted two cell cultures from clinically relevant, but dif-ferent cancer forms: pancreatic and triple-negative mammary adenocarcinomas. In spite of their different tissue origin, the two cell cultures appeared to similarly respond to the effects of the two metabolites, which were found to modulate in opposite ways the expres-sion of key genes involved in DNA repair by homologous recombination. As a conse-quence, changed efficacy of this repair pathway and modified response to PARP inhibi-tors were observed. Notably, our results also suggest that the counteracting effect between these two metabolites may be leveraged to address additional challenges limiting the suc-cess of anticancer therapies.