title: Cisplatin resistance associated with PARP hyperactivation.
abstract: Non-small cell lung carcinoma patients are frequently treated with cisplatin (CDDP), most often yielding temporary clinical responses. Here, we show that PARP1 is highly expressed and constitutively hyperactivated in a majority of human CDDP-resistant cancer cells of distinct histologic origin. Cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PAR(high)) responded to pharmacologic PARP inhibitors as well as to PARP1-targeting siRNAs by initiating a DNA damage response that translated into cell death following the activation of the intrinsic pathway of apoptosis. Moreover, PARP1-overexpressing tumor cells and xenografts displayed elevated levels of PAR, which predicted the response to PARP inhibitors in vitro and in vivo more accurately than PARP1 expression itself. Thus, a majority of CDDP-resistant cancer cells appear to develop a dependency to PARP1, becoming susceptible to PARP inhibitor-induced apoptosis.
authors.affiliation: U848, INSERM, France.
authors.forename: Judith
authors.initials: J
authors.lastname: Michels
authors.forename: Ilio
authors.initials: I
authors.lastname: Vitale
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Galluzzi
authors.forename: Julien
authors.initials: J
authors.lastname: Adam
authors.forename: Ken André
authors.initials: KA
authors.lastname: Olaussen
authors.forename: Oliver
authors.initials: O
authors.lastname: Kepp
authors.forename: Laura
authors.initials: L
authors.lastname: Senovilla
authors.forename: Ibtissam
authors.initials: I
authors.lastname: Talhaoui
authors.forename: Justine
authors.initials: J
authors.lastname: Guegan
authors.forename: David Pierre
authors.initials: DP
authors.lastname: Enot
authors.forename: Monique
authors.initials: M
authors.lastname: Talbot
authors.forename: Angélique
authors.initials: A
authors.lastname: Robin
authors.forename: Philippe
authors.initials: P
authors.lastname: Girard
authors.forename: Cédric
authors.initials: C
authors.lastname: Oréar
authors.forename: Delphine
authors.initials: D
authors.lastname: Lissa
authors.forename: Abdul Qader
authors.initials: AQ
authors.lastname: Sukkurwala
authors.forename: Pauline
authors.initials: P
authors.lastname: Garcia
authors.forename: Parviz
authors.initials: P
authors.lastname: Behnam-Motlagh
authors.forename: Kimitoshi
authors.initials: K
authors.lastname: Kohno
authors.forename: Gen Sheng
authors.initials: GS
authors.lastname: Wu
authors.forename: Catherine
authors.initials: C
authors.lastname: Brenner
authors.forename: Philippe
authors.initials: P
authors.lastname: Dessen
authors.forename: Murat
authors.initials: M
authors.lastname: Saparbaev
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.forename: Maria
authors.initials: M
authors.lastname: Castedo
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D010616:Phenanthrenes / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / 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: D000970:Antineoplastic Agents; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012333:RNA, Messenger; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D002945:Cisplatin