Wee1 inhibition potentiates Wip1-dependent p53-negative tumor cell death during chemotherapy

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RESEARCH PRODUCT

Wee1 inhibition potentiates Wip1-dependent p53-negative tumor cell death during chemotherapy

Anastasia R. Goloudina Anastasia R. Goloudina Elena Y. Kochetkova Marc Bardou Marc Bardou Arlette Hammann Arlette Hammann Oleg N. Demidov Oleg N. Demidov Sarah Richaud Sarah Richaud Carmen Garrido Carmen Garrido Olga A. Fedorova Nickolai A. Barlev Burhan Uyanik Burhan Uyanik V Clausse V Clausse

subject

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 Cisplatin 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

description

AbstractInactivation 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.

year	journal	country	edition	language
2016-04-14	Cell Death & Disease

10.1038/cddis.2016.96 http://europepmc.org/articles/PMC4855675