title: PARP targeting counteracts gliomagenesis through induction of mitotic catastrophe and aggravation of deficiency in homologous recombination in PTEN-mutant glioma.
abstract: Glioblastoma multiforme (GBM) is the most common primary brain tumour in adults and one of the most aggressive cancers. PARP-1 is a nuclear protein involved in multiple facets of DNA repair and transcriptional regulation. In this study we dissected the action of PARP inhibition in different GBM cell lines with either functional or mutated PTEN that confers resistance to diverse therapies. In PTEN mutant cells, PARP inhibition induced a severe genomic instability, exacerbated homologous recombination repair (HR) deficiency and down-regulated the Spindle Assembly Checkpoint (SAC) factor BUBR1, leading to mitotic catastrophe (MC). EGFR gene amplification also represents a signature of genetic abnormality in GBM. To more effectively target GBM cells, co-treatment with a PARP inhibitor and an EGFR blocker, erlotinib, resulted in a strong suppression of ERK1/2 activation and in vivo the combined effect elicited a robust reduction in tumour development. In conclusion, PARP inhibition targets PTEN-deficient GBM cells through accentuation of SAC repression and aggravation of HR deficiency, leading to the induction of genomic instability and eventually deriving to mitotic catastrophe (MC); the inhibition of PARP and co-treatment with an inhibitor of pro-survival pathways strongly retarded in vivo gliomagenesis.
authors.affiliation: Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain.
authors.forename: Jara
authors.initials: J
authors.lastname: Majuelos-Melguizo
authors.affiliation: Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain.
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Rodríguez
authors.affiliation: Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: López-Jiménez
authors.affiliation: Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Rodríguez-Vargas
authors.affiliation: Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Martí Martín-Consuegra
authors.affiliation: Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Serrano-Sáenz
authors.affiliation: CNRS, UMR8104, Paris, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Gavard
authors.affiliation: IBIMER, Centro de Investigación Biomédica, Universidad de Granada, Spain.
authors.forename: J Mariano Ruiz
authors.initials: JM
authors.lastname: de Almodóvar
authors.affiliation: Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain.
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Oliver
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D059765:Homologous Recombination; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008938:Mitosis; D009154:Mutation / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012333:RNA, Messenger; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: BUBR1; EGFR; PARP1; PTEN; genomic instability; glioblastoma; homologous recombination; mitotic catastrophe