{"doi":"10.1016/j.tranon.2025.102603","title":"Bmi-1 inhibition sensitizes head and neck cancer stem cells to cytotoxic chemotherapy","abstract":"• Bmi-1 enhance the resistance of cancer stem cells to cytotoxic chemotherapy. • Therapeutic targeting of Bmi-1 inhibits chemotherapy-induced cancer stemness. • Preclinical data suggest that patients with head and neck cancer might benefit from therapeutic inhibition of Bmi-1. Cancer stem cells (CSC) drive therapeutic resistance and recurrence in head and neck squamous cell carcinoma (HNSCC). We and others have shown that treatment with cytotoxic chemotherapy agents ( e.g. Cisplatin, Carboplatin) induce Bmi-1 expression and increase the fraction of highly tumorigenic CSC in HNSCC. Notably, Bmi-1 is a master regulator of stem cell self-renewal and DNA repair. The purpose of this work was to test whether therapeutic inhibition of Bmi-1 sensitizes HNSCC cancer stem cells to chemotherapy. HNSCC cells (UM-SCC-1,-22A,-22B) were treated with Cisplatin or Carboplatin and subjected to stemness analyses to evaluate the impact of Bmi-1 on chemoresistance. We observed that both, shRNA-mediated Bmi-1 silencing or pharmacologic inhibition of Bmi-1 with the small molecule inhibitor PTC596, blocked chemotherapy-induced cancer stemness ( i.e. increase in the fraction of ALDH high CD44 high cells), CSC self-renewal ( i.e. orosphere formation) and inhibited protective DNA damage responses in HNSCC. Further, it is known that high IL-6 serum levels correlate with poor HNSCC patient survival, and that platinum-based therapies induce IL-6 signaling. Here, we observed that Bmi-1 silencing (or PTC596 treatment) inhibited the IL-6R/STAT3 signaling pathway even in presence of platinum-based cytotoxic agents ( i.e. Cisplatin, Carboplatin). In vivo , Bmi-1 inhibition with PTC596 suppressed Cisplatin-mediated increase in the fraction of ALDH high CD44 high cells (cancer stemness). Collectively, these preclinical results demonstrate that Bmi-1 is a key mediator of head and neck cancer stemness and suggest that HNSCC patients might benefit from treatment with a Bmi-1 inhibitor combined with a conventional chemotherapeutic agent.","journal":"Translational Oncology","year":2025,"id":582963,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9538,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1495262,"name":"Shirley Zheng","orcid":null,"position":1,"is_corresponding":false},{"id":668733,"name":"Kristy A. Warner","orcid":null,"position":2,"is_corresponding":false},{"id":1494886,"name":"Jaqueline Vaz Vanini","orcid":"0000-0003-1969-5589","position":3,"is_corresponding":false},{"id":1076174,"name":"Ritu Somayaji","orcid":null,"position":4,"is_corresponding":false},{"id":1495263,"name":"Madelynn R. Johnson","orcid":null,"position":5,"is_corresponding":false},{"id":413857,"name":"Zhaocheng Zhang","orcid":"0000-0002-0095-6710","position":6,"is_corresponding":false},{"id":668080,"name":"Peter J. Polverini","orcid":"0000-0001-9832-967X","position":7,"is_corresponding":false},{"id":289993,"name":"Rogério M. Castilho","orcid":"0000-0001-5358-612X","position":8,"is_corresponding":false},{"id":110023,"name":"Alexander T. Pearson","orcid":"0000-0003-2801-7456","position":9,"is_corresponding":false},{"id":413859,"name":"Jacques E. Nör","orcid":"0000-0002-4056-0235","position":10,"is_corresponding":false},{"id":668078,"name":"Alexandra E. Herzog","orcid":"0000-0002-8386-8045","position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-19T02:58:59.653747Z","pmid":"41289700","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":[]}