Abstract
Simple SummaryMedulloblastoma and neuroblastoma are childhood tumors of the central nervous system or the peripheral nervous system, respectively. These are the most common and deadly tumors of childhood. A common genetic feature of medulloblastoma and neuroblastoma is frequent segmental gain or amplification of chromosome 17q. Located on chromosome 17q23.2 is PPM1D which encodes WIP1, a phosphatase that acts as a regulator of p53 and DNA repair. Overexpression of WIP1 correlates with poor patient prognosis. We investigated the effects of genetic or pharmacologic inhibition of WIP1 activity and found that medulloblastoma and neuroblastoma cells were strongly dependent on WIP1 expression for survival. We also tested a number of small molecule inhibitors of WIP1 and show that SL-176 was the most effective compound suppressing the growth of medulloblastoma and neuroblastoma in vitro and in vivo.Childhood medulloblastoma and high-risk neuroblastoma frequently present with segmental gain of chromosome 17q corresponding to aggressive tumors and poor patient prognosis. Located within the 17q-gained chromosomal segments is PPM1D at chromosome 17q23.2. PPM1D encodes a serine/threonine phosphatase, WIP1, that is a negative regulator of p53 activity as well as key proteins involved in cell cycle control, DNA repair and apoptosis. Here, we show that the level of PPM1D expression correlates with chromosome 17q gain in medulloblastoma and neuroblastoma cells, and both medulloblastoma and neuroblastoma cells are highly dependent on PPM1D expression for survival. Comparison of different inhibitors of WIP1 showed that SL-176 was the most potent compound inhibiting medulloblastoma and neuroblastoma growth and had similar or more potent effects on cell survival than the MDM2 inhibitor Nutlin-3 or the p53 activator RITA. SL-176 monotherapy significantly suppressed the growth of established medulloblastoma and neuroblastoma xenografts in nude mice. These results suggest that the development of clinically applicable compounds inhibiting the activity of WIP1 is of importance since PPM1D activating mutations, genetic gain or amplifications and/or overexpression of WIP1 are frequently detected in several different cancers.
Highlights
The mutational activation of proto-oncogenes or inactivation of tumor suppressor genes are essential processes during development of cancer [1]
phosphatase magnesium-dependent 1 delta (PPM1D) Expression Correlates with Chromosome 17q Gains in Medulloblastoma and
We examined the expression of PPM1D mRNA in a panel of cell lines, including both neuroblastoma and medulloblastoma, as well as the breast cancer cell lines MCF-7 and BT474 exhibiting PPM1D gene amplification [41], and one supratentorial primitive tumor (sPNET) cell line (PSFK-1) containing isochromosome 17
Summary
The mutational activation of proto-oncogenes or inactivation of tumor suppressor genes are essential processes during development of cancer [1]. The tumor suppressor gene, TP53, is one of the most commonly mutated genes in cancer. The p53 protein is a master regulator of cell growth and death by controlling DNA repair mechanisms, cell cycle progression and apoptosis [2]. Dysregulation of p53 results in genomic instability, uncontrolled cell division and inhibition of apoptosis [3,4]. Neuroblastoma and medulloblastoma are childhood tumors of the peripheral and central nervous system, respectively, that just like other childhood solid tumors infrequently harbor TP53 mutations [5]. P53 activity is commonly impaired in these tumors, and relapsed tumors demonstrate increased incidence of TP53 mutations [6,7]
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