title: A small molecule screen identifies an inhibitor of DNA repair inducing the degradation of TFIIH and the chemosensitization of tumor cells to platinum.
abstract: Nucleotide excision repair (NER) removes DNA lesions resulting from exposure to UV irradiation or chemical agents such as platinum-based drugs used as anticancer molecules. Pharmacological inhibition of NER is expected to enhance chemosensitivity but nontoxic NER inhibitors are rare. Using a drug repositioning approach, we identify spironolactone (SP), an antagonist of aldosterone, as a potent NER inhibitor. We found that SP promotes a rapid and reversible degradation of XPB, a subunit of transcription/repair factor TFIIH. Such degradation depends both on ubiquitin-activating enzyme and on the 26S proteasome. Supplementation of extracts from SP-treated cells with purified TFIIH restored TFIIH-dependent repair and transcription activities in vitro, demonstrating the specific impact of SP on two fundamental functions of TFIIH. Finally, SP potentiated the cytotoxicity of platinum derivatives toward tumor cells, making it a potential therapeutic and research tool.
authors: IGBMC, Department of Functional Genomics and Cancer, Equipe Labellisée Ligue 2014, CNRS/INSERM/Université de Strasbourg, BP 163, 67404 Illkirch Cedex, CU Strasbourg, France.
authors: Sergey
authors: S
authors: Alekseev
authors: Laboratory of Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, INSERM and Université Pierre et Marie Curie, UPCM, 4 Place Jussieu, 75005 Paris, France.
authors: Mériam
authors: M
authors: Ayadi
authors: IGBMC, Department of Functional Genomics and Cancer, Equipe Labellisée Ligue 2014, CNRS/INSERM/Université de Strasbourg, BP 163, 67404 Illkirch Cedex, CU Strasbourg, France.
authors: Laurent
authors: L
authors: Brino
authors: IGBMC, Department of Functional Genomics and Cancer, Equipe Labellisée Ligue 2014, CNRS/INSERM/Université de Strasbourg, BP 163, 67404 Illkirch Cedex, CU Strasbourg, France.
authors: Jean-Marc
authors: JM
authors: Egly
authors: Laboratory of Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, INSERM and Université Pierre et Marie Curie, UPCM, 4 Place Jussieu, 75005 Paris, France.
authors: Annette K
authors: AK
authors: Larsen
authors: IGBMC, Department of Functional Genomics and Cancer, Equipe Labellisée Ligue 2014, CNRS/INSERM/Université de Strasbourg, BP 163, 67404 Illkirch Cedex, CU Strasbourg, France. Electronic address: fredr@igbmc.fr.
authors: Frédéric
authors: F
authors: Coin
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology*; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D013148:Spironolactone / Q000737:chemistry / Q000494:pharmacology*; D051758:Transcription Factor TFIIH / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D000970:Antineoplastic Agents; D021122:Protein Subunits; D051758:Transcription Factor TFIIH; D013148:Spironolactone; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D044764:Ubiquitin-Activating Enzymes; D002945:Cisplatin