Targeting oncogenic WIP1 phosphatase sensitizes hypoxic breast cancer cells to doxorubicin induced apoptosis via activation of p53-p21 axis

Abstract

BackgroundOncogenic PPM1D/Wip1 phosphatase is negative regulator of chemotherapy responses. Hypoxia is a common feature of solid tumors associated with poor prognosis and resistance to radiotherapy and chemotherapy. AimHere, we evaluated the role of Wip1 in hypoxia mediated resistance to chemotherapy induced apoptosis or senescence in MCF-7 cells. MethodsPPM1D/Wip1 amplification and expression was assessed by qRT-PCR analysis. GSK283037 was used for Wip1 inhibition. Cell cycle analysis and Annexin V/7AAD assays were used to measure the effect of Wip1 inhibition in hypoxia Senescence was assessed by SA-β-gal activityand γ-H2AX phosphorylation. Western blotting was used to assess DDR signaling. ResultsTargeting Wip1 restored DDR signaling and G1/S check point through activation of p53-p21 in hypoxia. Inhibition of Wip1 is associated with decreased HIF-1α stabilization and sensitized cells for doxorubicin induced apoptosis but not for senescence. ConclusionOur findings suggest Wip1 as an attractive therapeutic target for hypoxic solid tumors.