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

Abstract : 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.
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https://hal-univ-bourgogne.archives-ouvertes.fr/hal-01444405
Contributeur : Lnc - Université de Bourgogne <>
Soumis le : mardi 24 janvier 2017 - 09:39:29
Dernière modification le : mercredi 10 juin 2020 - 14:06:51

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C Clausse, A Goloudina, B Uyanik, E Y Kochetkova, S Richaud, et al.. Wee1 inhibition potentiates Wip1-dependent p53-negative tumor cell death during chemotherapy.. Cell Death and Disease, Nature Publishing Group, 2016, 7 (4), pp.e2195. ⟨10.1038/cddis.2016.96⟩. ⟨hal-01444405⟩

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