Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition

Defective homologous recombination (HR) DNA repair imposed by BRCA1 or BRCA2 deficiency sensitizes cells to poly (ADP-ribose) polymerase (PARP)-1 inhibition and is currently exploited in clinical treatment of HR-deficient tumors. Here we show that mild hyperthermia (41-42.5 °C) induces degradation o...

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Vydáno v:	Proceedings of the National Academy of Sciences - PNAS Ročník 108; číslo 24; s. 9851
Hlavní autoři:	Krawczyk, Przemek M, Eppink, Berina, Essers, Jeroen, Stap, Jan, Rodermond, Hans, Odijk, Hanny, Zelensky, Alex, van Bree, Chris, Stalpers, Lukas J, Buist, Marrije R, Soullié, Thomas, Rens, Joost, Verhagen, Hence J M, O'Connor, Mark J, Franken, Nicolaas A P, Ten Hagen, Timo L M, Kanaar, Roland, Aten, Jacob A
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 14.06.2011
Témata:	Animals Benzoquinones - pharmacology BRCA2 Protein - genetics BRCA2 Protein - metabolism Cell Line Cell Line, Tumor Cells, Cultured DNA Repair DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Embryonic Stem Cells - drug effects Embryonic Stem Cells - metabolism Embryonic Stem Cells - radiation effects Female HeLa Cells Hot Temperature Humans Immunoblotting Lactams, Macrocyclic - pharmacology Mice Mice, Nude Neoplasms, Experimental - genetics Neoplasms, Experimental - metabolism Neoplasms, Experimental - pathology Phthalazines - pharmacology Piperazines - pharmacology Poly(ADP-ribose) Polymerase Inhibitors Poly(ADP-ribose) Polymerases - genetics Poly(ADP-ribose) Polymerases - metabolism Quinazolines - pharmacology Rats Recombination, Genetic - drug effects Recombination, Genetic - genetics Recombination, Genetic - radiation effects RNA Interference Transplantation, Heterologous Tumor Burden - drug effects
ISSN:	1091-6490, 1091-6490
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Popis
Shrnutí:	Defective homologous recombination (HR) DNA repair imposed by BRCA1 or BRCA2 deficiency sensitizes cells to poly (ADP-ribose) polymerase (PARP)-1 inhibition and is currently exploited in clinical treatment of HR-deficient tumors. Here we show that mild hyperthermia (41-42.5 °C) induces degradation of BRCA2 and inhibits HR. We demonstrate that hyperthermia can be used to sensitize innately HR-proficient tumor cells to PARP-1 inhibitors and that this effect can be enhanced by heat shock protein inhibition. Our results, obtained from cell lines and in vivo tumor models, enable the design of unique therapeutic strategies involving localized on-demand induction of HR deficiency, an approach that we term induced synthetic lethality.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1091-6490 1091-6490
DOI:	10.1073/pnas.1101053108