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

Przemek M Krawczyk; Berina Eppink; Jeroen Essers; Jan Stap; Hans Rodermond; Hanny Odijk; Alex Zelensky; Chris van Bree; Lukas J Stalpers; Marrije R Buist; Thomas Soullié; Joost Rens; Hence J M Verhagen; Mark J O'Connor; Nicolaas A P Franken; Timo L M Ten Hagen; Roland Kanaar; Jacob A Aten

doi:10.1073/pnas.1101053108

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

Proc Natl Acad Sci U S A. 2011 Jun 14;108(24):9851-6. doi: 10.1073/pnas.1101053108. Epub 2011 May 9.

Authors

Przemek M Krawczyk¹, Berina Eppink, Jeroen Essers, Jan Stap, Hans Rodermond, Hanny Odijk, Alex Zelensky, Chris van Bree, Lukas J Stalpers, Marrije R Buist, Thomas Soullié, Joost Rens, Hence J M Verhagen, Mark J O'Connor, Nicolaas A P Franken, Timo L M Ten Hagen, Roland Kanaar, Jacob A Aten

Affiliation

¹ Van Leeuwenhoek Centre for Advanced Microscopy-AMC, Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
BRCA2 Protein / genetics
BRCA2 Protein / metabolism*
Benzoquinones / pharmacology
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
RNA Interference
Rats
Recombination, Genetic / drug effects
Recombination, Genetic / genetics*
Recombination, Genetic / radiation effects
Transplantation, Heterologous
Tumor Burden / drug effects

Substances

BRCA2 Protein
Benzoquinones
DNA-Binding Proteins
Lactams, Macrocyclic
NU 1025
Phthalazines
Piperazines
Poly(ADP-ribose) Polymerase Inhibitors
Quinazolines
X-ray repair cross complementing protein 3
17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
Poly(ADP-ribose) Polymerases
olaparib