ArticleOncogene2013
5-Fluorouracil signaling through a calcium-calmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells.
Article in Oncogene, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 53 citations in OpenAlex.
- Reactivating necroptosis in colorectal cancer potentiates chemotherapy and antitumor immune responses.Cancer letters · 2026Article
- Exploring potential additive effects of 5-fluorouracil, thymoquinone, and coenzyme Q10 triple therapy on colon cancer cells in relation to glycolysis and redox status modulation.Journal of the Egyptian National Cancer Institute · 2025Article
- The Potential of Nuclear Pore Complexes in Cancer Therapy.Molecules (Basel, Switzerland) · 2024Review
- Glioblastoma Multiforme: Sensitivity to Antimicrobial Peptides LL-37 and PG-1, and Their Combination with Chemotherapy for Predicting the Overall Survival of Patients.Pharmaceutics · 2024Article
- 5-Fluorouracil in Combination with Calcium Carbonate Nanoparticles Loaded with Antioxidant Thymoquinone against Colon Cancer: Synergistically Therapeutic Potential and Underlying Molecular Mechanism.Antioxidants (Basel, Switzerland) · 2024Article
- Expression of molecular markers and synergistic anticancer effects of chemotherapy with antimicrobial peptides on glioblastoma cells.Cancer chemotherapy and pharmacology · 2024Article
- Proton-sensing ion channels, GPCRs and calcium signaling regulated by them: implications for cancer.Frontiers in cell and developmental biology · 2024Review
- Prognostic value of theTherapeutic advances in medical oncology · 2024Article
- Dysregulation of calcium homeostasis in cancer and its role in chemoresistance.Cancer drug resistance (Alhambra, Calif.) · 2024Review
- TRPV6 Channel Is Involved in Pancreatic Ductal Adenocarcinoma Aggressiveness and Resistance to Chemotherapeutics.Cancers · 2023Article
- Inhibition of GABAA receptors in intestinal stem cells prevents chemoradiotherapy-induced intestinal toxicity.The Journal of experimental medicine · 2022Article
- Targeting Thymidylate Synthase and tRNA-Derived Non-Coding RNAs Improves Therapeutic Sensitivity in Colorectal Cancer.Antioxidants (Basel, Switzerland) · 2022Article
- Article
- In Vitro Evaluation of the Cytotoxic Effect ofMolecules (Basel, Switzerland) · 2022Article
- Role of Calcium Homeostasis in Modulating EMT in Cancer.Biomedicines · 2021Review
- Advances in Intracellular Calcium Signaling Reveal Untapped Targets for Cancer Therapy.Biomedicines · 2021Review
- Chemopreventive Effect of 5-Flurouracil Polymeric Hybrid PLGA-Lecithin Nanoparticles against Colon Dysplasia Model in Mice and Impact on p53 Apoptosis.Biomolecules · 2021Article
- Targeting oncogenic Notch signaling with SERCA inhibitors.Journal of hematology & oncology · 2021Review
- Various Aspects of Calcium Signaling in the Regulation of Apoptosis, Autophagy, Cell Proliferation, and Cancer.International journal of molecular sciences · 2020Review
- The p38 MAPK Signaling Activation in Colorectal Cancer upon Therapeutic Treatments.International journal of molecular sciences · 2020Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
5-Fluorouracil (5-FU) is an anti-metabolite that is in clinical use for treatment of several cancers. In cells, it is converted into three distinct fluoro-based nucleotide analogs, which interfere with DNA synthesis and repair, leading to genome impairment and, eventually, apoptotic cell death. Current knowledge states that in certain cell types, 5-FU-induced stress is signaling through a p53-dependent induction of tumor necrosis factor-receptor oligomerization required for death-inducing signaling complex formation and caspase-8 activation. Here we establish a role of calcium (Ca(2+)) as a messenger for p53 activation in response to 5-FU. Using a combination of pharmacological and genetic approaches, we show that treatment of colon carcinoma cells stimulates entry of extracellular Ca(2+) through long lasting-type plasma membrane channels, which further directs posttranslational phosphorylation of at least three p53 serine residues (S15, S33 and S37) by means of calmodulin (CaM) activity. Obstructing this pathway by the Ca(2+)-chelator BAPTA (1,2-bis(o-aminophenoxy)ethane- N,N,N',N'-tetraacetic acid) or by inhibitors of CaM efficiently reduces 5-FU-induced caspase activities and subsequent cell death. Moreover, ectopic expression of p53 S15A in HCT116 p53(-/-) cells confirmed the importance of a Ca(2+)-CaM-p53 axis in 5-FU-induced extrinsic apoptosis. The fact that a widely used therapeutic drug, such as 5-FU, is operating via this pathway could provide new therapeutic intervention points, or specify new combinatorial treatment regimes.
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