WIP1 phosphatase as a potential therapeutic target in neuroblastoma
Nature-type p53-caused phosphatase 1 (WIP1) is really a serine/threonine phosphatase that negatively regulates multiple proteins involved with DNA damage response including p53, CHK2, Histone H2AX, and ATM, and contains been proven to become overexpressed or amplified in human cancers including breast and ovarian cancers. We examined WIP1 mRNA levels across multiple tumor types and located the greatest levels in cancer of the breast, leukemia, medulloblastoma and neuroblastoma. Neuroblastoma is definitely an solely TP53 wild type tumor at diagnosis and inhibition of p53 is needed for tumorigenesis. Neuroblastomas particularly have formerly been proven to possess 17q amplification, harboring the WIP1 (PPM1D) gene and connected with poor clinical outcome. We therefore searched for to find out whether inhibiting WIP1 having a selective antagonist, GSK2830371, can attenuate neuroblastoma cell growth through reactivation of p53 mediated tumor suppression. Neuroblastoma cell lines with wild-type TP53 alleles were highly responsive to GSK2830371 treatment, while cell lines with mutant TP53 were resistant against GSK2830371. Nearly all tested neuroblastoma cell lines with copy number gains from the PPM1D locus were also TP53 wild-type and responsive to GSK2830371A in comparison cell lines without any copy gain of PPM1D were included their sensitivity to WIP1 inhibition, using the primary determinant being TP53 mutational status. Since WIP1 is active in the cellular reaction to DNA damage and medicines utilized in neuroblastoma treatment induce apoptosis through DNA damage, we searched for to find out whether GSK2830371 could act synergistically with standard of care chemotherapeutics. Management of wild-type TP53 neuroblastoma cell lines with GSK2830371 and only doxorubicin or carboplatin led to enhanced cell dying, mediated through caspase 3/7 induction, when compared with either agent alone. Our data shows that WIP1 inhibition represents a singular therapeutic method of neuroblastoma that may be integrated with current chemotherapeutic approaches.