title: Induction of senescence by progesterone receptor-B activation in response to cAMP in ovarian cancer cells.
abstract: OBJECTIVE
  Progesterone receptor (PR) expression is a favorable prognostic marker in ovarian cancer. We previously demonstrated that the induction of PR-B by treatment with cAMP was associated with G0/G1 arrest of the cell cycle and growth inhibition in NIH 3T3 cells. In this study, we examined the effect of cAMP treatment on cell growth in Ras-transformed NIH3T3 cells and ovarian cancer cells.
  
  
  METHODS
  1) The levels of PR-B and cell cycle associated proteins (p21, p27 and Rb) following treatment with cAMP in the Ras-transformed NIH3T3 cells (K12V) and ovarian cancer cell lines (SKOV cells) were investigated by Western blots. 2) The effects of PR overexpression following treatment with cAMP or after infection of an adenovirus expressing PR-B on cell growth and tumorigenicity in a soft agar culture were examined.
  
  
  RESULTS
  1) Treatment with cAMP increased PR-B and p27 levels in K12V cells and inhibited cell growth by inducing premature senescence. Induction of senescence was specific to the transformed cells. 2) In SKOV cells, treatment with cAMP induced PR-B, p27 and p21 expression, reduced the level of phosphorylated Rb, caused accumulation of cells in the G0/G1 fraction of the cell cycle, and induced senescence. 3) Both anchorage-dependent and -independent SKOV cell growths were inhibited by cAMP treatment. 4) Induction of both the expression and transcriptional activity of PR-B is critical for the induction of senescence and suppression of tumorigenicity.
  
  
  CONCLUSIONS
  Treatment of cAMP, through activation of PR-B, induced senescence and suppressed tumorigenicity in ovarian cancer cells.
authors.affiliation: Department of Molecular Genetics, Division of Molecular and Cell Therapeutics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Takahashi
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Kato
authors.forename: Ayumi
authors.initials: A
authors.lastname: Kuboyama
authors.forename: Takafumi
authors.initials: T
authors.lastname: Inoue
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Aya
authors.initials: A
authors.lastname: Kuhara
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kinoshita
authors.forename: Satoru
authors.initials: S
authors.lastname: Takeda
authors.forename: Norio
authors.initials: N
authors.lastname: Wake
mesh_terms: D000818:Animals; D003994:Bucladesine / Q000494:pharmacology*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D005260:Female; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011980:Receptors, Progesterone / Q000096:biosynthesis*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D011980:Receptors, Progesterone; C097314:progesterone receptor B; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003994:Bucladesine