{"doi":"10.1111/jcmm.16874","title":"Imipramine impedes glioma progression by inhibiting YAP as a Hippo pathway independent manner and synergizes with temozolomide","abstract":"<jats:title>Abstract</jats:title><jats:p>Patients with malignant glioma often suffered from depression, which leads to an increased risk of detrimental outcomes. Imipramine, an FDA‐approved tricyclic antidepressant, has been commonly used to relieve depressive symptoms in the clinic. Recently, imipramine has been reported to participate in the suppression of tumour progression in several human cancers, including prostate cancer, colon cancer and lymphomas. However, the effect of imipramine on malignant glioma is largely unclear. Here, we show that imipramine significantly retarded proliferation of immortalized and primary glioma cells. Mechanistically, imipramine suppressed tumour proliferation by inhibiting yes‐associated protein (YAP), a recognized oncogene in glioma, independent of Hippo pathway. In addition to inhibiting YAP transcription, imipramine also promoted the subcellular translocation of YAP from nucleus into cytoplasm. Consistently, imipramine administration significantly reduced orthotopic tumour progression and prolonged survival of tumour‐bearing mice. Moreover, exogenous overexpression of YAP partially restored the inhibitory effect of imipramine on glioma progression. Most importantly, compared with imipramine or temozolomide (TMZ) monotherapy, combination therapy with imipramine and TMZ exhibited enhanced inhibitory effect on glioma growth both <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic>, suggesting the synergism of both agents. In conclusion, we found that tricyclic antidepressant imipramine impedes glioma progression by inhibiting YAP. In addition, combination therapy with imipramine and TMZ may potentially serve as promising anti‐glioma regimens, thus predicting a broad prospect of clinical application.</jats:p>","journal":"Journal of Cellular and Molecular Medicine","year":2021,"id":590706,"datarank":1.0773218580159765,"base_score":3.295836866004329,"endowment":3.295836866004329,"self_citation_contribution":0.4943755299006494,"citation_network_contribution":0.5829463281153271,"self_endowment_contribution":0.4943755299006494,"citer_contribution":0.5829463281153271,"corpus_percentile":null,"corpus_rank":null,"citation_count":26,"citer_count":22,"citers_with_citation_signal":16,"citers_with_endowment":16,"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":835969,"name":"Xiang Wang","orcid":"0000-0002-9629-3084","position":1,"is_corresponding":false},{"id":337596,"name":"Xu Wang","orcid":"0000-0001-8428-9339","position":2,"is_corresponding":false},{"id":820442,"name":"Di Wu","orcid":"0000-0002-6848-668X","position":3,"is_corresponding":false},{"id":1285205,"name":"Ji Qi","orcid":"0000-0003-4585-6534","position":4,"is_corresponding":false},{"id":831198,"name":"Yu Zhang","orcid":"0000-0001-5969-2388","position":5,"is_corresponding":false},{"id":1071445,"name":"Kai Wang","orcid":"0000-0003-4328-8799","position":6,"is_corresponding":false},{"id":563808,"name":"Ding Zhou","orcid":"0000-0002-3620-4035","position":7,"is_corresponding":false},{"id":1511311,"name":"Qing‐Ming Meng","orcid":null,"position":8,"is_corresponding":false},{"id":1511312,"name":"Er Nie","orcid":null,"position":9,"is_corresponding":false},{"id":555644,"name":"Qiang Wang","orcid":"0000-0002-7604-8153","position":10,"is_corresponding":false},{"id":1511313,"name":"Ru‐Tong Yu","orcid":null,"position":11,"is_corresponding":false},{"id":842282,"name":"Xiuping Zhou","orcid":"0000-0002-6663-8168","position":12,"is_corresponding":false},{"id":658651,"name":"Yan Wang","orcid":"0000-0001-7265-778X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Imipramine impedes glioma progression by inhibiting YAP as a Hippo pathway independent manner and synergizes with temozolomide","abstract":"<jats:title>Abstract</jats:title><jats:p>Patients with malignant glioma often suffered from depression, which leads to an increased risk of detrimental outcomes. Imipramine, an FDA‐approved tricyclic antidepressant, has been commonly used to relieve depressive symptoms in the clinic. Recently, imipramine has been reported to participate in the suppression of tumour progression in several human cancers, including prostate cancer, colon cancer and lymphomas. However, the effect of imipramine on malignant glioma is largely unclear. Here, we show that imipramine significantly retarded proliferation of immortalized and primary glioma cells. Mechanistically, imipramine suppressed tumour proliferation by inhibiting yes‐associated protein (YAP), a recognized oncogene in glioma, independent of Hippo pathway. In addition to inhibiting YAP transcription, imipramine also promoted the subcellular translocation of YAP from nucleus into cytoplasm. Consistently, imipramine administration significantly reduced orthotopic tumour progression and prolonged survival of tumour‐bearing mice. Moreover, exogenous overexpression of YAP partially restored the inhibitory effect of imipramine on glioma progression. Most importantly, compared with imipramine or temozolomide (TMZ) monotherapy, combination therapy with imipramine and TMZ exhibited enhanced inhibitory effect on glioma growth both <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic>, suggesting the synergism of both agents. In conclusion, we found that tricyclic antidepressant imipramine impedes glioma progression by inhibiting YAP. In addition, combination therapy with imipramine and TMZ may potentially serve as promising anti‐glioma regimens, thus predicting a broad prospect of clinical application.</jats:p>","is_dataset_classified":null,"base_score":3.295836866004329,"endowment":3.295836866004329,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"34469035","pmcid":"PMC8500960","openalex_id":"https://openalex.org/W3196415878","authors":[],"funders":[{"funder_name":"National Natural Science Foundation of China","grant_id":"81872053","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"81902526","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"82072770","title":null},{"funder_name":"Natural Science Foundation of Jiangsu Province","grant_id":"BK20201458","title":null}],"total_grants":4,"fwci":1.9843,"citation_percentile":0.85862719,"influential_citations":1,"citation_trend":[{"year":2021,"count":2},{"year":2022,"count":6},{"year":2023,"count":5},{"year":2024,"count":7},{"year":2025,"count":4},{"year":2026,"count":2}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://doi.org/10.1111/jcmm.16874","host_type":"journal"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500960","host_type":"GREEN"},{"url":"https://doi.org/10.1111/jcmm.16874","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1111/jcmm.16874","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/full-xml/10.1111/jcmm.16874","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/34469035","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/8500960","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC8500960","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC8500960?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Hippo pathway signaling and YAP/TAZ","Cancer-related Molecular Pathways","Ubiquitin and proteasome pathways","Medicine","Animals","Antineoplastic Agents","Cell Cycle Proteins","Cell Line, Tumor","Cell Proliferation","Disease Models, Animal","Dose-Response Relationship, Drug","Drug Synergism","Glioma","Humans","Imipramine","Intracellular Signaling Peptides and Proteins","Mice","Prognosis","Protein Serine-Threonine Kinases","Signal Transduction","Temozolomide","Transcription Factors","Treatment Outcome","Xenograft Model Antitumor Assays","Hippo Kinases"],"mesh_terms":["Temozolomide","Hippo Kinases","Animals","Antineoplastic Agents","Disease Models, Animal","Dose-Response Relationship, Drug","Drug Synergism","Glioma","Humans","Imipramine","Prognosis","Transcription Factors","Signal Transduction","Treatment Outcome","Protein Serine-Threonine Kinases","Cell Cycle Proteins","Xenograft Model Antitumor Assays","Cell Line, Tumor","Intracellular Signaling Peptides and Proteins","Cell Proliferation","Mice"],"keywords":["Imipramine","Temozolomide","Glioma","Cancer research","Pharmacology","Medicine","Oncogene","Antidepressant","Cancer","Internal medicine","Pathology","Cell cycle","Hippocampus","Proliferation","YAP"],"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":"2026-07-25T09:15:09.296864Z","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":[]}