title: Stimulation of lactate receptor (HCAR1) affects cellular DNA repair capacity.
abstract: Numerous G-protein coupled receptors have been reported to enhance cancer cell survival and resistance to clinically used chemotherapeutics. Recently, hydroxycarboxylic acid receptor 1 (HCAR1) was shown to drive lactate-dependent enhancement of cell survival and metastasis in pancreatic and breast cancers. Furthermore, our previous study confirmed the involvement of HCAR1 in lactate-related enhancement of DNA repair in cervical cancer cells. In the present study, we examined the possible mechanisms of HCAR1-mediated enhancement of DNA repair capacity. We observed that the HCAR1 agonist dihydroxybenzoic acid (DHBA) up-regulated BRCA1 (breast cancer type 1 susceptibility protein) and NBS1 (Nijmegen breakage syndrome 1) expression in HeLa cells. Moreover, HCAR1 silencing decreased mRNA and protein levels of BRCA1 by 30% and 20%, respectively. Immunocytochemical analyses of BRCA1, nibrin and DNA-PKcs indicated an increased accumulation of these proteins in cell nuclei after DHBA stimulation. Subsequently, these changes in the DNA repair protein levels translated into an enhanced DNA repair rate after doxorubicin treatment, as shown by γ-H2AX and comet assay experiments. In contrast, the down-regulation of HCAR1 decreased the efficiency of DNA repair. Finally, we observed the abrogation of DHBA-driven BRCA1 protein up-regulation and enhanced DNA repair following the preincubation of cells with the PKC inhibitor Gö6983. Taken together, our data indicate that lactate receptor/HCAR1 expression in cervical carcinoma cells may contribute to the modulation of cellular DNA repair mechanisms.
authors.affiliation: Laboratory of Cellular Immunology, Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland. Electronic address: wwagner@cbm.pan.pl.
authors.forename: Waldemar
authors.initials: W
authors.lastname: Wagner
authors.affiliation: Laboratory of Transcriptional Regulation, Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland.
authors.forename: Katarzyna D
authors.initials: KD
authors.lastname: Kania
authors.affiliation: Department of Molecular Cell Mechanisms, Medical University of Lodz, Poland.
authors.forename: Wojciech M
authors.initials: WM
authors.lastname: Ciszewski
mesh_terms: D019313:BRCA1 Protein / Q000187:drug effects / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D020552:Comet Assay; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D051747:DNA-Activated Protein Kinase / Q000187:drug effects / Q000235:genetics*; D004317:Doxorubicin / Q000633:toxicity; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D062385:Hydroxybenzoates / Q000494:pharmacology*; D007700:Kinetics; D009687:Nuclear Proteins / Q000187:drug effects / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D015398:Signal Transduction; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; C533610:HCAR1 protein, human; D062385:Hydroxybenzoates; C112156:NBN protein, human; D009687:Nuclear Proteins; D043562:Receptors, G-Protein-Coupled; D004317:Doxorubicin; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human
keywords: BRCA1; DHBA; DNA-PKcs; HCAR1; Lactate receptor; nibrin