ArticleJournal of experimental & clinical cancer research : CR2021
Choline kinase alpha impairment overcomes TRAIL resistance in ovarian cancer cells.
Article in Journal of experimental & clinical cancer research : CR, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 26 citations in OpenAlex.
- Subtype-specific mechanisms of lipid metabolism in gynecological malignancies and novel targeted intervention strategies (Review).Oncology letters · 2026Review
- Cytoplasmic TP53INP2 acts as an apoptosis partner in TRAIL treatment: the synergistic effect of TRAIL with venetoclax in TP53INP2-positive acute myeloid leukemia.Journal of experimental & clinical cancer research : CR · 2024Article
- PLA2G4A and ACHE modulate lipid profiles via glycerophospholipid metabolism in platinum-resistant gastric cancer.Journal of translational medicine · 2024Article
- Novel players in the development of chemoresistance in ovarian cancer: ovarian cancer stem cells, non-coding RNA and nuclear receptors.Cancer drug resistance (Alhambra, Calif.) · 2024Review
- Identification of a cholesterol metabolism-related prognostic signature for multiple myeloma.Scientific reports · 2023Article
- MALAT1 as a Regulator of the Androgen-Dependent Choline Kinase A Gene in the Metabolic Rewiring of Prostate Cancer.Cancers · 2022Article
- Phosphatidylcholine-Derived Lipid Mediators: The Crosstalk Between Cancer Cells and Immune Cells.Frontiers in immunology · 2022Review
- DNA Methylation of Human Choline Kinase Alpha Promoter-Associated CpG Islands in MCF-7 Cells.Genes · 2021Article
- Choline Kinase: An Unexpected Journey for a Precision Medicine Strategy in Human Diseases.Pharmaceutics · 2021Review
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Authors and funding
12 authors at 4 institutions in 1 country.
Funding
Abstract
backgroundCholine kinase-α (ChoKα/CHKA) overexpression and hyper-activation sustain altered choline metabolism conferring the cholinic phenotype to epithelial ovarian cancer (OC), the most lethal gynecological tumor. We previously proved that CHKA down-modulation reduced OC cell aggressiveness and increased sensitivity to in vitro chemotherapeutics' treatment also affecting intracellular content of one-carbon metabolites. In tumor types other than ovary, methionine decrease was shown to increase sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-receptor 2 triggering. These effects were suggestive of a potential role for ChoKα in regulating susceptibility to TRAIL cytokine.
methodsThe relationship between ChoKα/CHKA and TRAIL-receptor 2 (TRAIL-R2) expression was investigated in silico in OC patients' GEO datasets and in vitro in a panel of OC cell lines upon transient CHKA silencing (siCHKA). The effect of siCHKA on metabolites content was assessed by LC-MS. The triggered apoptotic signalling was studied following soluble-TRAIL or anti-TRAIL-R2 agonist antibody treatment. Lipid rafts were isolated by Triton X-100 fractionation. Preclinical ex vivo studies were performed in OC cells derived from patients' ascites using autologous PBLs as effectors and a bispecific anti-TRAIL-R2/anti-CD3 antibody as triggering agent.
resultsHere we demonstrate that siCHKA specifically overcomes resistance to TRAIL-mediated apoptosis in OC cells. Upon siCHKA we detected: a significant sensitization to caspase-dependent apoptosis triggered by both soluble TRAIL and anti-TRAIL-R2 agonist antibody, a specific increase of TRAIL-R2 expression and TRAIL-R2 relocation into lipid rafts. In siCHKA-OC cells the acquired TRAIL sensitivity was completely reverted upon recovery of ChoKα expression but, at variance of other tumor cell types, TRAIL sensitivity was not efficiently phenocopied by methionine deprivation. Of note, we were also able to show that siCHKA sensitized tumor cells derived ex vivo from OC patients' ascites to the cytotoxic activity of autologous lymphocytes redirected by a bispecific anti-TRAIL-R2/anti-CD3 antibody.
conclusionsOur findings suggest that ChoKα/CHKA impairment, by restoring drug-induced or receptor-mediated cell death, could be a suitable therapeutic strategy to be used in combination with chemotherapeutics or immunomodulators to improve OC patients' outcome.
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