title: PGA1-induced apoptosis involves specific activation of H-Ras and N-Ras in cellular endomembranes.
abstract: The cyclopentenone prostaglandin A1 (PGA1) is an inducer of cell death in cancer cells. However, the mechanism that initiates this cytotoxic response remains elusive. Here we report that PGA1 triggers apoptosis by a process that entails the specific activation of H- and N-Ras isoforms, leading to caspase activation. Cells without H- and N-Ras did not undergo apoptosis upon PGA1 treatment; in these cells, the cellular demise was rescued by overexpression of either H-Ras or N-Ras. Consistently, the mutant H-Ras-C118S, defective for binding PGA1, did not produce cell death. Molecular analysis revealed a key role for the RAF-MEK-ERK signaling pathway in the apoptotic process through the induction of calpain activity and caspase-12 cleavage. We propose that PGA1 evokes a specific physiological cell death program, through H- and N-Ras, but not K-Ras, activation at endomembranes. Our results highlight a novel mechanism that may be of potential interest for tumor treatment.
authors.affiliation: Unidad de Biología Celular, Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III, Madrid 28220, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Anta
authors.affiliation: Unidad de Biología Celular, Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III, Madrid 28220, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Pérez-Rodríguez
authors.affiliation: Unidad de Biología Celular, Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III, Madrid 28220, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Castro
authors.affiliation: Unidad de Biología Celular, Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III, Madrid 28220, Spain.
authors.forename: C A
authors.initials: CA
authors.lastname: García-Domínguez
authors.affiliation: Fundación Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Ibiza
authors.affiliation: Unidad de Biología Celular, Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III, Madrid 28220, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Martínez
authors.affiliation: Unidad de Biología Celular, Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III, Madrid 28220, Spain.
authors.forename: L M
authors.initials: LM
authors.lastname: Durá
authors.affiliation: Unidad de Biología Celular, Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III, Madrid 28220, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Hernández
authors.affiliation: Unidad de Biología Celular, Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III, Madrid 28220, Spain.
authors.forename: T
authors.initials: T
authors.lastname: Gragera
authors.affiliation: Unidad de Biología Celular, Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III, Madrid 28220, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Peña-Jiménez
authors.affiliation: Unidad de Biología Celular, Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III, Madrid 28220, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Yunta
authors.affiliation: Unidad de Biología Celular, Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III, Madrid 28220, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Zarich
authors.affiliation: Departamento de Biologia Molecular, Facultad de Medicina, Instituto de Biomedicina y Biotecnología de Cantabria, Consejo Superior de Investigaciones Cientificas (CSIC)-IDICAN, Universidad de Cantabria, Santander 39011, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Crespo
authors.affiliation: Departamento de Biología Celular e Inmunología, Centro de Biología Molecular Severo Ochoa (CBMSO), CSIC-UAM, Madrid 28049, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Serrador
authors.affiliation: Centro de Investigación del Cancer, IBMCC (CSIC-USAL), Universidad de Salamanca, Salamanca 37007, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Santos
authors.affiliation: Instituto de Investigaciones Biomédicas 'Alberto Sols', Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Arturo Duperier 4, Madrid 28029, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Muñoz
authors.affiliation: Unidad de Biología Celular, Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III, Madrid 28220, Spain.
authors.forename: J L
authors.initials: JL
authors.lastname: Oliva
authors.affiliation: Unidad de Biología Celular, Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III, Madrid 28220, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Rojas-Cabañeros
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002154:Calpain / Q000378:metabolism; D045744:Cell Line, Tumor; D003545:Cysteine / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D011454:Prostaglandins A / Q000494:pharmacology*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D011454:Prostaglandins A; D048049:Extracellular Signal-Regulated MAP Kinases; D002154:Calpain; D018631:ras Proteins; D003545:Cysteine; C100573:prostaglandin A1