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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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 24; p. 9851
Main Authors: 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
Format: Journal Article
Language:English
Published: United States 14.06.2011
Subjects:
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
Online Access:Get more information
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Summary: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.
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ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.1101053108