Epidermal growth factor triggers an original, caspase-independent pituitary cell death with heterogeneous phenotype

• Published in: Molecular biology of the cell 2004-11, Vol.15 (11), p.4938-4948
• Main Authors: Fombonne, Joanna, Reix, Stéphanie, Rasolonjanahary, Ramahefarizo, Danty, Emmanuelle, Thirion, Sylvie, Laforge-Anglade, Geneviéve, Bosler, Olivier, Mehlen, Patrick, Enjalbert, Alain, Krantic, Slavica
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Blotting, Western; Caspases - metabolism; Cell Death; Cell Line; Cell Separation; Chromatin - metabolism; Cytochromes c - metabolism; Cytoplasm - metabolism; DNA Fragmentation; Epidermal Growth Factor - metabolism; Flow Cytometry; Immunohistochemistry; Life Sciences; Microscopy, Confocal; Microscopy, Electron, Transmission; Mitochondria - pathology; Phenotype; Pituitary Gland - cytology; Pituitary Gland - metabolism; Pituitary Gland - pathology; Proto-Oncogene Proteins c-bcl-2 - metabolism; Rats; Time Factors; Transfection
• ISSN: 1059-1524; 1939-4586
• DOI: 10.1091/mbc.E04-07-0601

Programmed cell death (PCD) is physiologically involved in the regulation of cell division and differentiation. It encompasses caspase-dependent mitochondrial and nonmitochondrial pathways. Additional caspase-independent pathways have been characterized in mitochondrial PCDs but remain hypothetical in nonmitochondrial PCDs. Epidermal growth factor (EGF) has been shown to inhibit division of pituitary somato-lactotrope cells occurring in parallel with EGF-mediated differentiation of these precursors into lactotrope cells. We show here that in somato-lactotrope pituitary cell line GH4C1, EGF triggers a PCD characterized by an apoptosis-like DNA fragmentation, insensitivity to broad-range caspase inhibitors, and absence of either cytochrome c or apoptosis-inducing factor release from mitochondria. Dying cells display loose chromatin clustering and numerous cytoplasmic vacuoles, a fraction of which are autophagic, thus conferring a heterogeneous phenotype to this PCD. Moreover, overexpression of cell death inhibitor Bcl-2 prevented not only the EGF-induced PCD but also its prodifferentiation effects, thus pointing to a mechanistic relationship existing between these two phenomena. Overall, the characterized differentiation-linked cell death represents an original form of caspase-independent PCD. The mechanisms underlying this PCD involve combinatorial engagement of discrete death effectors leading to a heterogeneous death phenotype that might be evolutionary related to PCD seen during the differentiation of some unicellular organisms.