title: Inhibition of Ubiquitin-specific Peptidase 8 Suppresses Adrenocorticotropic Hormone Production and Tumorous Corticotroph Cell Growth in AtT20 Cells.
abstract: BACKGROUND
  Two recent whole-exome sequencing researches identifying somatic mutations in the ubiquitin-specific protease 8 (USP8) gene in pituitary corticotroph adenomas provide exciting advances in this field. These mutations drive increased epidermal growth factor receptor (EGFR) signaling and promote adrenocorticotropic hormone (ACTH) production. This study was to investigate whether the inhibition of USP8 activity could be a strategy for the treatment of Cushing's disease (CD).
  
  
  METHODS
  The anticancer effect of USP8 inhibitor was determined by testing cell viability, colony formation, apoptosis, and ACTH secretion. The immunoblotting and quantitative reverse transcription polymerase chain reaction were conducted to explore the signaling pathway by USP8 inhibition.
  
  
  RESULTS
  Inhibition of USP8-induced degradation of receptor tyrosine kinases including EGFR, EGFR-2 (ERBB2), and Met leading to a suppression of AtT20 cell growth and ACTH secretion. Moreover, treatment with USP8 inhibitor markedly induced AtT20 cells apoptosis.
  
  
  CONCLUSIONS
  Inhibition of USP8 activity could be an effective strategy for CD. It might provide a novel pharmacological approach for the treatment of CD.
authors: Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors: Fang-Fang
authors: FF
authors: Jian
authors: Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors: Yun-Feng
authors: YF
authors: Li
authors: Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors: Yu-Fan
authors: YF
authors: Chen
authors: Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors: Hong
authors: H
authors: Jiang
authors: Department of Neurosurgery, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China.
authors: Xiao
authors: X
authors: Chen
authors: Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors: Li-Li
authors: LL
authors: Zheng
authors: Department of Neurosurgery, Shanghai Pituitary Tumor Center, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China.
authors: Yao
authors: Y
authors: Zhao
authors: Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors: Wei-Qing
authors: WQ
authors: Wang
authors: Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors: Guang
authors: G
authors: Ning
authors: Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors: Liu-Guan
authors: LG
authors: Bian
authors: Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors: Qing-Fang
authors: QF
authors: Sun
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D010450:Endopeptidases / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D007192:Indenes / Q000494:pharmacology; D051379:Mice; D011719:Pyrazines / Q000494:pharmacology; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: C550627:9-oxo-9H-indeno(1,2-b)pyrazine-2,3-dicarbonitrile; D056827:Endosomal Sorting Complexes Required for Transport; D004791:Enzyme Inhibitors; D007192:Indenes; D011719:Pyrazines; D000324:Adrenocorticotropic Hormone; D066246:ErbB Receptors; D010450:Endopeptidases; D043222:Ubiquitin Thiolesterase; C541536:Usp8 protein, mouse