{"doi":"10.1042/bj20111236","title":"The non-steroidal anti-inflammatory drug indomethacin activates the eIF2α kinase PKR, causing a translational block in human colorectal cancer cells","abstract":"<jats:p>The NSAID (non-steroidal anti-inflammatory drug) indomethacin, a cyclo-oxygenase-1 and -2 inhibitor with anti-inflammatory and analgesic properties, is known to possess anticancer activity against CRC (colorectal cancer) and other malignancies in humans; however, the mechanism underlying the anticancer action remains elusive. In the present study we show that indomethacin selectively activates the dsRNA (double-stranded RNA)-dependent protein kinase PKR in a cyclo-oxygenase-independent manner, causing rapid phosphorylation of eIF2α (the α-subunit of eukaryotic translation initiation factor 2) and inhibiting protein synthesis in colorectal carcinoma and other types of cancer cells. The PKR-mediated translational block was followed by inhibition of CRC cell proliferation and apoptosis induction. Indomethacin did not affect the activity of the eIF2α kinases PERK (PKR-like endoplasmic reticulum-resident kinase), GCN2 (general control non-derepressible-2) and HRI (haem-regulated inhibitor kinase), and induced eIF2α phosphorylation in PERK-knockout and GCN2-knockout cells, but not in PKR-knockout cells or in human PKR-silenced CRC cells, identifying PKR as a selective target for indomethacin-induced translational inhibition. The fact that indomethacin induced PKR activity in vitro, an effect reversed by the PKR inhibitor 2-aminopurine, suggests a direct effect of the drug in kinase activation. The results of the present study identify PKR as a novel target of indomethacin, suggesting new scenarios on the molecular mechanisms underlying the pleiotropic activity of this traditional NSAID.</jats:p>","journal":"Biochemical Journal","year":2012,"id":21543,"datarank":3.0474999953476036,"base_score":4.007333185232471,"endowment":4.007333185232471,"self_citation_contribution":0.6010999777848708,"citation_network_contribution":2.4464000175627327,"self_endowment_contribution":0.6010999777848708,"citer_contribution":2.4464000175627327,"corpus_percentile":null,"corpus_rank":null,"citation_count":54,"citer_count":52,"citers_with_citation_signal":48,"citers_with_endowment":48,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":138305,"name":"Carla Amici","orcid":null,"position":1,"is_corresponding":false},{"id":138306,"name":"Mara Angelini","orcid":null,"position":2,"is_corresponding":false},{"id":138307,"name":"Chiara Fracassi","orcid":null,"position":3,"is_corresponding":false},{"id":138308,"name":"Giuseppe Belardo","orcid":null,"position":4,"is_corresponding":false},{"id":138309,"name":"M. Gabriella Santoro","orcid":null,"position":5,"is_corresponding":false},{"id":138304,"name":"Claudia Brunelli","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":4.007333185232471,"endowment":4.007333185232471,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"22268531","pmcid":null,"openalex_id":"https://openalex.org/W2061056854","authors":[],"funders":[],"total_grants":0,"fwci":1.4778,"citation_percentile":0.81295928,"influential_citations":1,"citation_trend":[{"year":2013,"count":6},{"year":2014,"count":3},{"year":2015,"count":2},{"year":2016,"count":3},{"year":2017,"count":2},{"year":2018,"count":6},{"year":2019,"count":3},{"year":2020,"count":7},{"year":2021,"count":7},{"year":2022,"count":2},{"year":2023,"count":3},{"year":2024,"count":6},{"year":2025,"count":3},{"year":2026,"count":1}],"oa_status":"closed","license":null,"oa_locations":[{"url":"https://portlandpress.com/biochemj/article-pdf/443/2/379/672964/bj4430379.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1042/bj20111236","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/22268531","host_type":"repository"},{"url":"http://hdl.handle.net/2108/65872","host_type":"repository"}],"fields_of_study":["RNA regulation and disease","Endoplasmic Reticulum Stress and Disease","Adenosine and Purinergic Signaling","Medicine","Biology","Anti-Inflammatory Agents, Non-Steroidal","Cell Line, Tumor","Cell Proliferation","Cisplatin","Colonic Neoplasms","Enzyme Activation","Humans","Indomethacin","Protein Biosynthesis","eIF-2 Kinase"],"mesh_terms":["Anti-Inflammatory Agents, Non-Steroidal","Cisplatin","Colonic Neoplasms","Enzyme Activation","Humans","Indomethacin","Protein Biosynthesis","eIF-2 Kinase","Cell Line, Tumor","Cell Proliferation"],"keywords":["Protein kinase R","EIF-2 kinase","Kinase","Protein kinase A","Integrated stress response","Phosphorylation","eIF2","Biology","Pharmacology","Chemistry","Cancer research","Cell biology","Cyclin-dependent kinase 2","Translation (biology)","Biochemistry","Messenger RNA"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-06-06T16:11:40.483793Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}