ArticleCell communication and signaling : CCS2015
L- and D-lactate enhance DNA repair and modulate the resistance of cervical carcinoma cells to anticancer drugs via histone deacetylase inhibition and hydroxycarboxylic acid receptor 1 activation.
Article in Cell communication and signaling : CCS, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 119 papers.
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Who cites it
119 citing papers in PubMed, 181 citations in OpenAlex.
- Effectiveness of vaginal probioticsAging · 2024Trial
- Prognostic Significance of Serum Lactic Acid, Lactate Dehydrogenase, and Albumin Levels in Patients with Metastatic Colorectal Cancer.BioMed research international · 2018Trial
- Histone deacetylases in cancer metabolic reprogramming.Experimental & molecular medicine · 2026Review
- Review
- The dual role of gastric microbiota dysbiosis in gastric cancer progression and therapy.International journal of clinical oncology · 2026Review
- Metabolic activation of LDHA by ERRα represses inflammasome-dependent pyroptosis and promotes ovarian cancer chemoresistance.Cell death & disease · 2026Article
- Lactylation enzymes in cancer: Mechanisms and novel therapeutic approaches (Review).Oncology letters · 2026Review
- Lactate metabolism and lactylation in cancer: from pathogenesis to therapeutic advances.Signal transduction and targeted therapy · 2026Review
- ATM promotes PFKP nuclear translocation to balance glycolysis and homologous recombination repair.Nucleic acids research · 2026Article
- Glyoxalase 2 Drives D-Lactate Oncometabolite Signaling to Promote Prostate Cancer Aggressiveness via FAK/Src Activation.Antioxidants (Basel, Switzerland) · 2026Article
- Lactate-lactylation in tumor angiogenesis and progression: mechanisms, biomarker potential, and therapeutic implications.Biomarker research · 2026Review
- Post-translational modification networks in tumor radiosensitivity: mechanistic insights and therapeutic opportunities.Journal of translational medicine · 2026Review
- Extracellular vesicles as modulators of cancer metabolism and microenvironment.Extracellular vesicles and circulating nucleic acids · 2026Review
- Lactic Acid Drives ESM1 to Attenuate DNA Damage and CD8+ T Cell Infiltration in Cancer.Oncology research · 2026Article
- The microbiota-host metabolic axis in cervical cancer: from homeostatic disruption to mechanisms of therapy resistance.Frontiers in cellular and infection microbiology · 2026Review
- Regulation of drug resistance in bladder urothelial carcinoma by tumor aerobic glycolysis.Journal of translational medicine · 2025Review
- Microbiota-directed lactic acid depleting nanoenzyme reactivates antitumor immunity and chemosensitivity in hypoxic tumor.Materials today. Bio · 2025Article
- Lactate Enhances Non-Homologous End Joining Repair and Chemoresistance Through Facilitating XRCC4-LIG4 Complex Assembly in Ovarian Cancer.Biomedicines · 2025Article
- Lactate at the crossroads of tumor metabolism and immune escape: a new frontier in cancer therapy.Journal of translational medicine · 2025Review
- Lactate and lactylation: molecular insights into histone and non-histone lactylation in tumor progression, tumor immune microenvironment, and therapeutic strategies.Biomarker research · 2025Review
59 more citing papers are in PubMed but not listed here.
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3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe consideration of lactate as an active metabolite is a newly emerging and attractive concept. Recently, lactate has been reported to regulate gene transcription via the inhibition of histone deacetylases (HDACs) and survival of cancer cells via hydroxycarboxylic acid receptor 1 (HCAR1). This study examined the role of L- and D-lactate in the DNA damage response in cervical cancer cells.
methodsThree cervical cancer cell lines were examined: HeLa, Ca Ski and C33A. The inhibitory activity of lactate on HDACs was analysed using Western blot and biochemical methods. The lactate-mediated stimulation of DNA repair and cellular resistance to neocarzinostatin, doxorubicin and cisplatin were studied using γ-H2AX, comet and clonogenic assays. HCAR1 and DNA repair gene expression was quantified by real-time PCR. DNA-PKcs activity and HCAR1 protein expression were evaluated via immunocytochemistry and Western blot, respectively. HCAR1 activation was investigated by measuring intracellular cAMP accumulation and Erk phosphorylation. HCAR1 expression was silenced using shRNA.
resultsL- and D-lactate inhibited HDACs, induced histone H3 and H4 hyperacetylation, and decreased chromatin compactness in HeLa cells. Treating cells with lactate increased LIG4, NBS1, and APTX expression by nearly 2-fold and enhanced DNA-PKcs activity. Based on γ-H2AX and comet assays, incubation of cells in lactate-containing medium increased the DNA repair rate. Furthermore, clonogenic assays demonstrated that lactate mediates cellular resistance to clinically used chemotherapeutics. Western blot and immunocytochemistry showed that all studied cell lines express HCAR1 on the cellular surface. Inhibiting HCAR1 function via pertussis toxin pretreatment partially abolished the effects of lactate on DNA repair. Down-regulating HCAR1 decreased the efficiency of DNA repair, abolished the cellular response to L-lactate and decreased the effect of D-lactate. Moreover, HCAR1 shRNA-expressing cells produced significantly lower mRNA levels of monocarboxylate transporter 4. Finally, the enhancement of DNA repair and cell survival by lactate was suppressed by pharmacologically inhibiting monocarboxylate transporters using the inhibitor α-cyano-4-hydroxycinnamic acid (α-CHCA).
conclusionsOur data indicate that L- and D-lactate present in the uterine cervix may participate in the modulation of cellular DNA damage repair processes and in the resistance of cervical carcinoma cells to anticancer therapy.
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