Abstract
Ewing Sarcoma is an aggressive malignancy of bone and soft tissue affecting children and young adults. Ewing Sarcoma is driven by EWS/Ets fusion oncoproteins, which cause widespread alterations in gene expression in the cell. Dysregulation of receptor tyrosine kinase signaling, particularly involving IGF-1R, also plays an important role in Ewing Sarcoma pathogenesis. However, the basis of this dysregulation, including the relative contribution of EWS/Ets-dependent and independent mechanisms, is not well understood. In the present study, we identify variable expression of two modifiers of PI3K signaling activity, PIK3R3 and PTEN, in Ewing Sarcoma, and examine the consequences of this on PI3K pathway regulation and oncogenic phenotypes. Our findings indicate that PIK3R3 plays a growth-promotional role in Ewing Sarcoma, but suggest that this role is not strictly dependent on regulation of PI3K pathway activity. We further show that expression of PTEN, a well-established, potent tumor suppressor, is lost in a subset of Ewing Sarcomas, and that this loss strongly correlates with high baseline PI3K pathway activity in cell lines. In support of functional importance of PTEN loss in Ewing Sarcoma, we show that re-introduction of PTEN into two different PTEN-negative Ewing Sarcoma cell lines results in downregulation of PI3K pathway activity, and sensitization to the IGF-1R small molecule inhibitor OSI-906. Our findings also suggest that PTEN levels may contribute to sensitivity of Ewing Sarcoma cells to the microtubule inhibitor vincristine, a relevant chemotherapeutic agent in this cancer. Our studies thus identify PIK3R3 and PTEN as modifiers of oncogenic phenotypes in Ewing Sarcoma, with potential clinical implications.
Highlights
Ewing Sarcoma is the second most common bone and soft tissue malignancy in children and young adults [1]
We noted loss of PTEN protein expression in one cell line (EWS502), which was associated with striking upregulation of baseline PI3K pathway activity
To determine whether PI3KR3 plays a pro-oncogenic role in Ewing Sarcoma, as recently shown in other cancers [22, 23], we examined the effects of its depletion in Ewing Sarcoma cells
Summary
Ewing Sarcoma is the second most common bone and soft tissue malignancy in children and young adults [1]. Ewing Sarcoma is driven by recurrent EWS/Ets oncogenic fusions, which, through gain-of-function transcriptional activity, and possibly other mechanisms, result in PLOS ONE | DOI:10.1371/journal.pone.0116895. PI3K Pathway in Ewing Sarcoma dysregulation of expression of many genes, as well as non-coding RNAs [2,3,4,5]. The ultimate outcome of oncogene-driven dysregulation of gene expression is promotion of the malignant phenotype. It is appreciated that some Ewing Sarcomas manifest genetic alterations other than an EWS/Ets oncogenic fusion, for example loss of function of p53 and the p16INK4/p14ARF locus [6]. The occurrence and frequency of other such alterations, and their potential contribution to the Ewing Sarcoma malignant phenotype, largely remain to be characterized
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