title: Bromocriptine induces parapoptosis as the main type of cell death responsible for experimental pituitary tumor shrinkage.
abstract: Bromocriptine (Bc) produces pituitary tumoral mass regression which induces the cellular death that was classically described as apoptosis. However, recent works have related that other mechanisms of cell death could also be involved in the maintenance of physiological and pathological pituitary homeostasis. The aim of this study was to evaluate and characterize the different types of cell death in the involution induced by Bc in experimental rat pituitary tumors. The current study demonstrated that Bc induced an effective regression of estrogen induced pituitary tumors by a mechanism identified as parapoptosis. This alternative cell death was ultrastructurally recognized by extensive cytoplasmic vacuolization and an increased cell electron density, represented around 25% of the total pituitary cells counted. Furthermore, the results obtained from biochemical assays did not correspond to the criteria of apoptosis or necrosis. We also investigated the participation of p38, ERK1/2 and PKC delta in the parapoptotic pathway. An important observation was the significant increase in phosphorylated forms of these MAPKs, the holoenzyme and catalytic fragments of PKC delta in nuclear fractions after Bc administration compared to control and estrogen treated rats. Furthermore, the immunolocalization at ultrastructural level of these kinases showed a similar distribution pattern, with a prevalent localization at nuclear level in lactotrophs from Bc treated rats. In summary, we determined that parapoptosis is the predominant cell death type involved in the regression of pituitary tumors in response to Bc treatment, and may cause the activation of PKC delta, ERK1/2 and p38.
authors: Centro de Microscopía Electrónica, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Argentina. cpalmeri@cmefcm.uncor.edu
authors: Claudia Mariela
authors: CM
authors: Palmeri
authors: Juan Pablo
authors: JP
authors: Petiti
authors: Liliana del Valle
authors: Ldel V
authors: Sosa
authors: Silvina
authors: S
authors: Gutiérrez
authors: Ana Lucía
authors: AL
authors: De Paul
authors: Jorge Humberto
authors: JH
authors: Mukdsi
authors: Alicia Inés
authors: AI
authors: Torres
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001971:Bromocriptine / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D048370:MAP Kinase Kinase 2 / Q000502:physiology; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D015175:Prolactinoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D051745:Protein Kinase C-delta / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D001971:Bromocriptine; D051745:Protein Kinase C-delta; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D048370:MAP Kinase Kinase 2