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

作者：Victor Clausse, Anastasia R. Goloudina, Burhan Uyanik, Elena Kochetkova, Sarah Richaud, Olga Fedorova, Arlette Hammann, Marc Bardou, Nickolai A. Barlev, Carmen Garrido, Oleg N. Demidov · 发表于：Cell Death and Disease · 年份：2016 · DOI：10.1038/cddis.2016.96 · 被引用次数：25 · 研究领域：Cancer-related Molecular Pathways、Cell death mechanisms and regulation、Microtubule and mitosis dynamics

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 ...