Wee1 inhibition potentiates Wip1-dependent p53-negative tumor cell death during chemotherapy
| Autor: | Anastasia R. Goloudina, Elena Y. Kochetkova, Marc Bardou, Arlette Hammann, Oleg N. Demidov, Sarah Richaud, Carmen Garrido, Olga A. Fedorova, Nickolai A. Barlev, Burhan Uyanik, V Clausse |
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| Přispěvatelé: | Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Institute of Cytology of the Russian Academy of Science (St. Petersburg), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Fondation ARC, laboratoire d'excellence ARC, La Ligue Contre le Cancer CCIR-GE (14-15-00636 ), fondation scientifique russe, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Wip1
Apoptosis Cell Cycle Proteins Pharmacology MESH: G2 Phase Cell Cycle Checkpoints Histones MESH : Phosphorylation Mice MESH : Cell Cycle Proteins MESH: Animals MESH: Tumor Suppressor Protein p53 MESH: Histones Kinase Tp53 mutations MESH : Mice Transgenic 3. Good health Protein Phosphatase 2C Survival Rate MESH : Antineoplastic Agents H2ax phosphorylation P53 activation MESH: Protein Phosphatase 2C RNA Interference MESH : Colorectal Neoplasms MESH : Carrier Proteins Histone H2ax MESH: Mitochondria Immunology Human fibroblasts MESH: Carrier Proteins Antineoplastic Agents MESH: Protein-Tyrosine Kinases MESH: Protein-Serine-Threonine Kinases MESH : Cisplatin 03 medical and health sciences MESH: Cell Cycle Proteins Genotoxic stress MESH : Protein-Tyrosine Kinases Humans MESH : Histones Anticancer Therapy MESH: DNA Damage Cisplatin MESH: Humans MESH: Phosphorylation [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology MESH : Humans MESH : Nuclear Proteins 030104 developmental biology Cancer cell MESH: Antineoplastic Agents Carrier Proteins MESH: Nuclear Proteins MESH : Apoptosis Dna-damage response 0301 basic medicine Cancer Research MESH: Caspase 3 MESH : Caspase 3 Phosphorylation Cytotoxicity MESH : DNA Damage Sensitization medicine.diagnostic_test Caspase 3 Nuclear Proteins Protein-Tyrosine Kinases MESH : Survival Rate Mitochondria G2 Phase Cell Cycle Checkpoints Wee1 medicine.anatomical_structure MESH : Protein Phosphatase 2C Original Article MESH : Mitochondria Colorectal Neoplasms medicine.drug MESH : Protein-Serine-Threonine Kinases MESH: Cell Line Tumor MESH: Survival Rate MESH: Mice Transgenic MESH: RNA Interference Phosphatase Mice Transgenic [SDV.BC]Life Sciences [q-bio]/Cellular Biology Biology Protein Serine-Threonine Kinases Flow cytometry Cellular and Molecular Neuroscience Cell Line Tumor MESH : Mice medicine Animals MESH: Mice MESH : Cell Line Tumor MESH: Apoptosis Cell Biology MESH : Tumor Suppressor Protein p53 MESH: Cisplatin Cancer research biology.protein MESH : Animals MESH : G2 Phase Cell Cycle Checkpoints MESH : RNA Interference Tumor Suppressor Protein p53 MESH: Colorectal Neoplasms DNA Damage |
| Zdroj: | Cell Death & Disease Cell Death and Disease Cell Death and Disease, Nature Publishing Group, 2016, 7 (4), pp.e2195. 〈http://www.nature.com/cddis/journal/v7/n4/full/cddis201696a.html〉. 〈10.1038/cddis.2016.96〉 Cell Death and Disease, Nature Publishing Group, 2016, 7 (4), pp.e2195. ⟨10.1038/cddis.2016.96⟩ |
| ISSN: | 2041-4889 |
| DOI: | 10.1038/cddis.2016.96〉 |
| Popis: | Inactivation of p53 found in more than half of human cancers is often associated with increased tumor resistance to anti-cancer therapy. We have previously shown that overexpression of the phosphatase Wip1 in p53-negative tumors sensitizes them to chemotherapeutic agents, while protecting normal tissues from the side effects of anti-cancer treatment. In this study, we decided to search for kinases that prevent Wip1-mediated sensitization of cancer cells, thereby interfering with efficacy of genotoxic anti-cancer drugs. To this end, we performed a flow cytometry-based screening in order to identify kinases that regulated the levels of γH2AX, which were used as readout. Another criterion of the screen was increased sensitivity of p53-negative tumor cells to cisplatin (CDDP) in a Wip1-dependent manner. We have found that a treatment with a low dose (75 nM) of MK-1775, a recently described specific chemical inhibitor of Wee1, decreases CDDP-induced H2AX phosphorylation in p53-negative cells and enhances the Wip1-sensitization of p53-negative tumors. We were able to reduce CDDP effective concentration by 40% with a combination of Wip1 overexpression and Wee1 kinase inhibition. We have observed that Wee1 inhibition potentiates Wip1-dependent tumor sensitization effect by reducing levels of Hipk2 kinase, a negative regulator of Wip1 pathway. In addition, during CDDP treatment, the combination of Wee1 inhibition and Wip1 overexpression has a mild but significant protective effect in normal cells and tissues. Our results indicate that inhibition of the negative regulators of Wip1 pathway, Wee1 and Hipk2, in p53-negative tumors could potentiate efficiency of chemotherapeutic agents without concomitant increase of cytotoxicity in normal tissues. The development and clinical use of Wee1 and Hipk1 kinase chemical inhibitors might be a promising strategy to improve anti-cancer therapy. |
| Databáze: | OpenAIRE |
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