PARP targeting counteracts gliomagenesis through induction of mitotic catastrophe and aggravation of deficiency in homologous recombination in PTEN-mutant glioma

• DOI: 10.18632/oncotarget.2993
• Publication Date: 2015-09-15T07:56:51Z
• Authors: Jara Majuelos-Mel...; María Isabel Rodr...; Laura López-Jiménez; Jose M. Rodríguez...; Juan M. Martí Mar...; Santiago Serrano-...; Julie Gavard; J. Mariano Ruiz d...; F. Javier Oliver
• Keywords: Mitotic catastrophe; Synthetic Lethality

// Jara Majuelos-Melguizo 1 , María Isabel Rodríguez Laura López-Jiménez Jose M. Rodríguez-Vargas Juan Martí Martín-Consuegra Santiago Serrano-Sáenz Julie Gavard 3 J. Mariano Ruiz de Almodóvar 2 and F. Javier Oliver Instituto Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain IBIMER, Centro Investigación Biomédica, Universidad CNRS, UMR8104, Paris, France Correspondence: Oliver, email: Keywords : BUBR1, Mitotic catastrophe, Glioblastoma, Homologous recombination, PARP1, PTEN, genomic instability, EGFR Received August 18, 2014 Accepted December 10, Published 11, Abstract Glioblastoma multiforme (GBM) is the most common primary brain tumour in adults one of aggressive cancers. PARP-1 a nuclear protein involved multiple facets DNA repair transcriptional regulation. In this study we dissected action PARP inhibition different GBM cell lines with either functional or mutated PTEN that confers resistance to diverse therapies. mutant cells, induced severe exacerbated homologous recombination (HR) deficiency down-regulated Spindle Assembly Checkpoint (SAC) factor leading mitotic catastrophe (MC). gene amplification also represents signature genetic abnormality GBM. To more effectively target co-treatment inhibitor an blocker, erlotinib, resulted strong suppression ERK1/2 activation vivo combined effect elicited robust reduction development. conclusion, targets PTEN-deficient cells through accentuation SAC repression aggravation HR deficiency, induction instability eventually deriving (MC); pro-survival pathways strongly retarded gliomagenesis.