{"doi":"10.1016/j.celrep.2022.111223","title":"Pituitary adenomas evade apoptosis via noxa deregulation in Cushing’s disease","abstract":"Sporadic pituitary adenomas occur in over 10% of the population. Hormone-secreting adenomas, including those causing Cushing's disease (CD), cause severe morbidity and early mortality. Mechanistic studies of CD are hindered by a lack of in vitro models and control normal human pituitary glands. Here, we surgically annotate adenomas and adjacent normal glands in 25 of 34 patients. Using single-cell RNA sequencing (RNA-seq) analysis of 27594 cells, we identify CD adenoma transcriptomic signatures compared with adjacent normal cells, with validation by bulk RNA-seq, DNA methylation, qRT-PCR, and immunohistochemistry. CD adenoma cells include a subpopulation of proliferating, terminally differentiated corticotrophs. In CD adenomas, we find recurrent promoter hypomethylation and transcriptional upregulation of PMAIP1 (encoding pro-apoptotic BH3-only bcl-2 protein noxa) but paradoxical noxa downregulation. Using primary CD adenoma cell cultures and a corticotroph-enriched mouse cell line, we find that selective proteasomal inhibition with bortezomib stabilizes noxa and induces apoptosis, indicating its utility as an anti-tumor agent.","journal":"Cell Reports","year":2022,"id":243368,"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":34,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8573,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":515082,"name":"Reinier Alvarez","orcid":"0000-0003-0694-5526","position":1,"is_corresponding":false},{"id":390778,"name":"Patrick A. Fletcher","orcid":"0000-0003-0227-5895","position":2,"is_corresponding":false},{"id":875155,"name":"Debjani Mandal","orcid":"0000-0003-4151-1838","position":3,"is_corresponding":false},{"id":272179,"name":"Kory Johnson","orcid":"0000-0001-7678-3812","position":4,"is_corresponding":false},{"id":494123,"name":"Weiwei Wu","orcid":"0000-0003-4260-2803","position":5,"is_corresponding":false},{"id":470115,"name":"Abdel Elkahloun","orcid":"0000-0002-1749-740X","position":6,"is_corresponding":false},{"id":322333,"name":"Paúl E. Clavijo","orcid":"0000-0003-2279-2515","position":7,"is_corresponding":false},{"id":260382,"name":"Clint Allen","orcid":"0000-0001-6586-5804","position":8,"is_corresponding":false},{"id":331837,"name":"Dragan Maric","orcid":"0000-0003-2912-7921","position":9,"is_corresponding":false},{"id":484166,"name":"Abhik Ray‐Chaudhury","orcid":null,"position":10,"is_corresponding":false},{"id":349611,"name":"Sharika Rajan","orcid":null,"position":11,"is_corresponding":false},{"id":240507,"name":"Zied Abdullaev","orcid":"0000-0001-6345-2088","position":12,"is_corresponding":false},{"id":875729,"name":"Diana Nwokoye","orcid":null,"position":13,"is_corresponding":false},{"id":13200,"name":"Kenneth Aldape","orcid":"0000-0001-5119-7550","position":14,"is_corresponding":false},{"id":417806,"name":"Lynnette K. Nieman","orcid":"0000-0003-0534-8025","position":15,"is_corresponding":false},{"id":287856,"name":"Constantine A. Stratakis","orcid":"0000-0002-4058-5520","position":16,"is_corresponding":false},{"id":233850,"name":"Stanko S. Stojilković","orcid":"0000-0002-7329-7488","position":17,"is_corresponding":false},{"id":356394,"name":"Prashant Chittiboina","orcid":"0000-0001-9349-4756","position":18,"is_corresponding":false},{"id":409813,"name":"David T. Asuzu","orcid":"0000-0001-7011-479X","position":0,"is_corresponding":true}],"reference_count":99,"raw_metadata":null,"created_at":"2026-07-19T00:23:16.032700Z","pmid":"36001971","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":[]}