Abstract
The wild-type p53-induced phosphatase 1 (WIP1) is a serine/threonine phosphatase that negatively regulates multiple proteins involved in DNA damage response including p53, CHK2, Histone H2AX, and ATM, and it has been shown to be overexpressed or amplified in human cancers including breast and ovarian cancers. We examined WIP1 mRNA levels across multiple tumor types and found the highest levels in breast cancer, leukemia, medulloblastoma and neuroblastoma. Neuroblastoma is an exclusively TP53 wild type tumor at diagnosis and inhibition of p53 is required for tumorigenesis. Neuroblastomas in particular have previously been shown to have 17q amplification, harboring the WIP1 (PPM1D) gene and associated with poor clinical outcome. We therefore sought to determine whether inhibiting WIP1 with 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 sensitive to GSK2830371 treatment, while cell lines with mutant TP53 were resistant to GSK2830371. The majority of tested neuroblastoma cell lines with copy number gains of the PPM1D locus were also TP53 wild-type and sensitive to GSK2830371A; in contrast cell lines with no copy gain of PPM1D were mixed in their sensitivity to WIP1 inhibition, with the primary determinant being TP53 mutational status. Since WIP1 is involved in the cellular response to DNA damage and drugs used in neuroblastoma treatment induce apoptosis through DNA damage, we sought to determine whether GSK2830371 could act synergistically with standard of care chemotherapeutics. Treatment of wild-type TP53 neuroblastoma cell lines with both GSK2830371 and either doxorubicin or carboplatin resulted in enhanced cell death, mediated through caspase 3/7 induction, as compared to either agent alone. Our data suggests that WIP1 inhibition represents a novel therapeutic approach to neuroblastoma that could be integrated with current chemotherapeutic approaches.
Highlights
The p53 pathway plays a critical role in maintaining the genomic fidelity of stem cell populations, including neural stem/ progenitor cells [1,2]
wild-type p53-induced phosphatase 1 (WIP1) mRNA is Overexpressed in Neuroblastoma and Medulloblastoma
During our initial characterization of WIP1 inhibitor’s cellular activity [33], we noted that sensitive cell lines fell within two broad categories: (i) hematological malignancies with a high frequency of wild-type TP53 but normal PPM1D copy number and expression, exemplified by AML, and (ii) those derived from solid tumors with both wild-type TP53 and aberrantly high WIP1 levels
Summary
The p53 pathway plays a critical role in maintaining the genomic fidelity of stem cell populations, including neural stem/ progenitor cells [1,2]. Late stage tumors often show loss of phosphorylation of DNA damage responsive proteins, suggesting that inactivation of this pathway is a prerequisite for cancer progression [9,10]. WIP1 has been shown to play a role in the homeostatic downregulation of resolved DNA damage responses in various healthy tissues, and acts as an oncogenic inhibitor of multiple tumor suppressors during cancer progression, highlighting the importance of WIP1 in maintaining genome stability. Activating germline mutations in the PPM1D gene have recently been associated with predisposition to breast and ovarian cancer [27]. These carboxy terminal truncating mutations have been identified in pediatric gliomas and colorectal tumors [26,28]
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