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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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS Jg. 108; H. 24; S. 9851 |
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| Format: | Journal Article |
| Sprache: | Englisch |
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| ISSN: | 1091-6490, 1091-6490 |
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| 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. |
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| AbstractList | 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. 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.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. |
| Author | Rens, Joost Zelensky, Alex Verhagen, Hence J M Eppink, Berina van Bree, Chris Stalpers, Lukas J Franken, Nicolaas A P Ten Hagen, Timo L M Krawczyk, Przemek M Rodermond, Hans Soullié, Thomas Essers, Jeroen Buist, Marrije R O'Connor, Mark J Kanaar, Roland Odijk, Hanny Stap, Jan Aten, Jacob A |
| Author_xml | – sequence: 1 givenname: Przemek M surname: Krawczyk fullname: Krawczyk, Przemek M organization: Van Leeuwenhoek Centre for Advanced Microscopy-AMC, Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands – sequence: 2 givenname: Berina surname: Eppink fullname: Eppink, Berina – sequence: 3 givenname: Jeroen surname: Essers fullname: Essers, Jeroen – sequence: 4 givenname: Jan surname: Stap fullname: Stap, Jan – sequence: 5 givenname: Hans surname: Rodermond fullname: Rodermond, Hans – sequence: 6 givenname: Hanny surname: Odijk fullname: Odijk, Hanny – sequence: 7 givenname: Alex surname: Zelensky fullname: Zelensky, Alex – sequence: 8 givenname: Chris surname: van Bree fullname: van Bree, Chris – sequence: 9 givenname: Lukas J surname: Stalpers fullname: Stalpers, Lukas J – sequence: 10 givenname: Marrije R surname: Buist fullname: Buist, Marrije R – sequence: 11 givenname: Thomas surname: Soullié fullname: Soullié, Thomas – sequence: 12 givenname: Joost surname: Rens fullname: Rens, Joost – sequence: 13 givenname: Hence J M surname: Verhagen fullname: Verhagen, Hence J M – sequence: 14 givenname: Mark J surname: O'Connor fullname: O'Connor, Mark J – sequence: 15 givenname: Nicolaas A P surname: Franken fullname: Franken, Nicolaas A P – sequence: 16 givenname: Timo L M surname: Ten Hagen fullname: Ten Hagen, Timo L M – sequence: 17 givenname: Roland surname: Kanaar fullname: Kanaar, Roland – sequence: 18 givenname: Jacob A surname: Aten fullname: Aten, Jacob A |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/21555554$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | 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 |
| Title | Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition |
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