title: Aphidicolin inhibits cell proliferation via the p53-GADD45β pathway in AtT-20 cells.
abstract: Cushing's disease is primarily caused by pituitary corticotroph adenomas, which autonomically secrete adrenocorticotropic hormone (ACTH). ACTH production may be associated with tumor cell proliferation; however, the effects of cell cycle progression on ACTH production and cell proliferation are little known in corticotroph tumor cells. A DNA polymerase inhibitor, aphidicolin, arrests cells at the entrance to the S phase and blocks the cell cycle; aphidicolin also induces apoptosis in tumor cells. In the present study, we determined ACTH production and cell proliferation of AtT-20 corticotroph tumor cells following treatment with aphidicolin. Aphidicolin decreased proopiomelanocortin mRNA levels in AtT-20 cells and the levels of ACTH in the culture medium of these cells. Aphidicolin also decreased cell proliferation and induced apoptosis in AtT-20 cells. Fluorescence-activated cell sorting analyses revealed that this agent increased the percentage of G0/G1 phase cells, and decreased S phase cells. Aphidicolin decreased the phosphorylation of cyclic adenosine monophosphate response element-binding protein and Akt. Aphidicolin increased the levels of tumor protein 27 (p27) and 53 (p53), while it decreased cyclin E levels. Aphidicolin also increased the mRNA levels of the stress response gene growth arrest and DNA damage-inducible 45β (GADD45β), a putative downstream target of p53. The p53 knockdown increased GADD45β mRNA levels. The GADD45β knockdown inhibited the decreases in cell proliferation. Thus, aphidicolin inhibits cell proliferation via the p53-GADD45β pathway in AtT-20 cells.
authors.affiliation: Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kageyama
authors.forename: Aya
authors.initials: A
authors.lastname: Sugiyama
authors.forename: Shingo
authors.initials: S
authors.lastname: Murasawa
authors.forename: Yuko
authors.initials: Y
authors.lastname: Asari
authors.forename: Kanako
authors.initials: K
authors.lastname: Niioka
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Oki
authors.forename: Makoto
authors.initials: M
authors.lastname: Daimon
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism*; D016590:Aphidicolin / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000097642:GADD45 Proteins
chemical_list: D000324:Adrenocorticotropic Hormone; D000943:Antigens, Differentiation; D016590:Aphidicolin; D011333:Pro-Opiomelanocortin; D051057:Proto-Oncogene Proteins c-akt; D016159:Tumor Suppressor Protein p53; C490125:Gadd45b protein, mouse; D000097642:GADD45 Proteins