title: Activation of a non-genomic Pim-1/Bad-Pser75 module is required for an efficient pro-survival effect of Bcl-xL induced by androgen in LNCaP cells.
abstract: The present report investigated the pathway(s) involved in the inhibition of apoptosis by the synthetic androgen, R1881 in serum-starved LNCaP cells exposed to the pi3K inhibitor, LY294002. R1881 blocked LY294002-induced apoptosis through the inhibition of Bak activation via an increase in Bcl-xL transcription and protein expression. In addition, R1881 treatment enhanced the stability of the Pim-1 kinase, resulting in the inhibition of the activation of the BH3-only protein Bad through its phosphorylation at ser75. Pharmacological inhibition of the Pim-1 kinase activity with quercetagetin, a highly selective Pim-1 inhibitor, prevented R1881-mediated increase in Bad phosphorylation and restored cell sensitivity to LY294002-induced apoptosis despite the increase in Bcl-xL expression. These results demonstrate for the first time that the inhibition of LY294002-induced apoptosis by androgen is a function of an androgen receptor-dependent genomic signaling pathway leading to an increase in Bcl-xL expression as well as a non-genomic, Pim-1-dependent, signaling pathway mediated via phosphorylation of Bad at ser75.
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore 119260, Singapore.
authors.forename: Jaspal Kaur
authors.initials: JK
authors.lastname: Kumar
authors.forename: Ryan Yueh Shyang
authors.initials: RY
authors.lastname: Ping
authors.forename: Huey Fern
authors.initials: HF
authors.lastname: Teong
authors.forename: Shijie
authors.initials: S
authors.lastname: Goh
authors.forename: Marie-Véronique
authors.initials: MV
authors.lastname: Clément
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016895:Culture Media, Serum-Free; D004789:Enzyme Activation / Q000187:drug effects; D004795:Enzyme Stability / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D015741:Metribolone / Q000494:pharmacology*; D009025:Morpholines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D051573:Proto-Oncogene Proteins c-pim-1 / Q000737:chemistry / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000737:chemistry* / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000728:Androgens; D002867:Chromones; D016895:Culture Media, Serum-Free; D009025:Morpholines; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D015741:Metribolone; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D012694:Serine; D051057:Proto-Oncogene Proteins c-akt; D051573:Proto-Oncogene Proteins c-pim-1