Fiche publication
Date publication
avril 2016
Journal
Cell death & disease
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BARDOU Marc
,
Dr GARRIDO Carmen
,
Dr DEMIDOV Oleg
Tous les auteurs :
Clausse V, Goloudina AR, Uyanik B, Kochetkova EY, Richaud S, Fedorova OA, Hammann A, Bardou M, Barlev NA, Garrido C, Demidov ON
Lien Pubmed
Résumé
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.
Mots clés
Animals, Antineoplastic Agents, pharmacology, Apoptosis, drug effects, Carrier Proteins, antagonists & inhibitors, Caspase 3, metabolism, Cell Cycle Proteins, antagonists & inhibitors, Cell Line, Tumor, Cisplatin, pharmacology, Colorectal Neoplasms, drug therapy, DNA Damage, drug effects, G2 Phase Cell Cycle Checkpoints, drug effects, Histones, metabolism, Humans, Mice, Mice, Transgenic, Mitochondria, metabolism, Nuclear Proteins, antagonists & inhibitors, Phosphorylation, drug effects, Protein Phosphatase 2C, genetics, Protein-Serine-Threonine Kinases, antagonists & inhibitors, Protein-Tyrosine Kinases, antagonists & inhibitors, RNA Interference, Survival Rate, Tumor Suppressor Protein p53, deficiency
Référence
Cell Death Dis. 2016 Apr;7:e2195
