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Pituitary adenomas evade apoptosis via noxa deregulation in Cushing's disease.
Asuzu, David T; Alvarez, Reinier; Fletcher, Patrick A; Mandal, Debjani; Johnson, Kory; Wu, Weiwei; Elkahloun, Abdel; Clavijo, Paul; Allen, Clint; Maric, Dragan; Ray-Chaudhury, Abhik; Rajan, Sharika; Abdullaev, Zied; Nwokoye, Diana; Aldape, Kenneth; Nieman, Lynnette K; Stratakis, Constantine; Stojilkovic, Stanko S; Chittiboina, Prashant.
Afiliação
  • Asuzu DT; Neurosurgery Unit for Pituitary and Inheritable Diseases, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, Room 3D20, Bethesda, MD 20892, USA; Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
  • Alvarez R; Neurosurgery Unit for Pituitary and Inheritable Diseases, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, Room 3D20, Bethesda, MD 20892, USA; Florida International University Herbert Wertheim College of Medicine, Miami, FL, USA.
  • Fletcher PA; Laboratory of Biological Modeling, National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, MD, USA.
  • Mandal D; Neurosurgery Unit for Pituitary and Inheritable Diseases, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, Room 3D20, Bethesda, MD 20892, USA.
  • Johnson K; DIR Bioinformatics Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
  • Wu W; Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, MD, USA.
  • Elkahloun A; Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, MD, USA.
  • Clavijo P; Translational Tumor Immunology Program, National Institute on Deafness and Other Communication Disorders, Bethesda, MD, USA.
  • Allen C; Translational Tumor Immunology Program, National Institute on Deafness and Other Communication Disorders, Bethesda, MD, USA.
  • Maric D; Flow and Imaging Cytometry Core Facility, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
  • Ray-Chaudhury A; Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA; Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA.
  • Rajan S; Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA.
  • Abdullaev Z; Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA.
  • Nwokoye D; Neurosurgery Unit for Pituitary and Inheritable Diseases, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, Room 3D20, Bethesda, MD 20892, USA.
  • Aldape K; Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA.
  • Nieman LK; Section on Translational Endocrinology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA.
  • Stratakis C; Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.
  • Stojilkovic SS; Section on Cellular Signaling, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.
  • Chittiboina P; Neurosurgery Unit for Pituitary and Inheritable Diseases, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, Room 3D20, Bethesda, MD 20892, USA; Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
Cell Rep ; 40(8): 111223, 2022 08 23.
Article em En | MEDLINE | ID: mdl-36001971
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Hipofisárias / Adenoma / Hipersecreção Hipofisária de ACTH Limite: Animals / Humans Idioma: En Revista: Cell Rep Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Hipofisárias / Adenoma / Hipersecreção Hipofisária de ACTH Limite: Animals / Humans Idioma: En Revista: Cell Rep Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos