Lactate dehydrogenase inhibition affects homologous recombination repair independently of cell metabolic asset; implications for anticancer treatment

• Published in: Biochimica et biophysica acta. General subjects Vol. 1865; no. 1; p. 129760
• Main Authors: Balboni, Andrea, Govoni, Marzia, Rossi, Valentina, Roberti, Marinella, Cavalli, Andrea, Di Stefano, Giuseppina, Manerba, Marcella
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2021
• Subjects: Antineoplastic Agents - pharmacology; assets; Cancer cell metabolism; Cell Line, Tumor; DNA; DNA damage; DNA repair; drug resistance; drugs; energy metabolism; Enzyme Inhibitors - pharmacology; glucose; Glycolysis; Glycolysis - drug effects; Homologous recombination; Humans; L-Lactate Dehydrogenase - antagonists & inhibitors; L-Lactate Dehydrogenase - metabolism; Lactate; Lactate dehydrogenase; neoplasm cells; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Olaparib; Phthalazines - pharmacology; Piperazines - pharmacology; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Recombinational DNA Repair - drug effects; Glycolysis; Cancer cell metabolism; Lactate dehydrogenase; Olaparib; Lactate; Homologous recombination
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2020.129760

Cancer cells show highly increased glucose utilization which, among other cancer-essential functions, was found to facilitate DNA repair. Lactate dehydrogenase (LDH) activity is pivotal for supporting the high glycolytic flux of cancer cells; to our knowledge, a direct contribution of this enzyme in the control of DNA integrity was never investigated. In this paper, we looked into a possible LDH-mediated regulation of homologous recombination (HR) repair. We identified two cancer cell lines with different assets in energy metabolism: either based on glycolytic ATP or on oxidative reactions. In cells with inhibited LDH, we assessed HR function by applying four different procedures. Our findings revealed an LDH-mediated control of HR, which was observed independently of cell metabolic asset. Since HR inhibition is known to make cancer cells responsive to PARP inhibitors, in both the cellular models we finally explored the effects of a combined inhibition of LDH and PARP. The obtained results suggest for LDH a central role in cancer cell biology, not merely linked to the control of energy metabolism. The involvement of LDH in the DNA damage response could suggest new drug combinations to obtain improved antineoplastic effects. Several evidences have correlated the metabolic features of cancer cells with drug resistance and LDH inhibition has been repeatedly shown to increase the antineoplastic power of chemotherapeutics. By shedding light on the processes linking cell metabolism to the control of DNA integrity, our findings also give a mechanistic explanation to these data. •The increased glycolytic rate of cancer cells facilitates DNA repair and confers resistance to chemotherapeutic agents.•LDH is a key enzyme in maintaining the glycolytic flux of cancer cells•Inhibition of LDH was found to dampen homologous recombination repair and increase the antineoplastic efficacy of Olaparib