Abstract
Resisting cellular senescence and becoming immortal is a pre-requisite step in the tumorigenic transformation of a cell. In this chapter we describe a novel mechanism by which inhibition of a key phosphatase can induce cellular senescence in the aggressive brain tumor, Glioblastoma Multiforme (GBM). We also provide an overview of recently published data suggesting additional mechanisms of senescence observed in this tumor type. Epidermal Growth Factor Receptor (EGFR) signaling is frequently altered during glioblastoma pathogenesis. An important downstream modulator of this signal cascade is Src Homology domain-containing Phosphatase 2 (SHP2/PTPN11). The Cancer Genome Atlas (TCGA) data demonstrates SHP2 to be mutated in 2% of the GBM’s studied. Both mutations identified are likely to be activating mutations. We found that the four subgroups of GBM as defined by TCGA differed significantly with regard to expression level of specific phosphatases by comparative marker analysis. Surprisingly, the four subgroups can be defined solely on the basis of phosphatase expression by principle component analysis. This result suggests that critical phosphatases are responsible for modulation of specific molecular pathways within each subgroup. SHP2 constitutes one of the 12 phosphatases that define the classical subgroup. We confirmed the biological significance of this phosphatase by siRNA knockdown. The loss of cell viability induced by SHP2 silencing could not be explained by a significant increase in apoptosis alone, as demonstrated by TUNEL and propidium iodide staining. SHP2 silencing, however, did induce an increase in β-galactosidase staining and significant morphological changes. Propidium iodide staining also showed SHP2 silencing to reduce the population of cells in G2/M and S-phase. Since G1 arrest is also a marker of cellular senescence these data suggest that the inhibitory effect of SHP2 silencing is largely due to increased senescence rather than necrosis or apoptosis. Our data suggests that SHP2 may in part promote the growth of glioblastoma cells by suppression of cellular senescence, a phenomenon not previously described. Since it is becoming clear that both accelerated senescence and conventional growth arrest are likely to represent alternative options to apoptosis in GBM cells, it is feasible that as more selective inhibitors of SHP2 become commercially available they should be considered as a therapeutic strategy for glioblastoma.
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Sturla, LM., Zinn, P., Kasper, E. (2013). Suppression of Cellular Senescence in Glioblastoma: Role of Src Homology Domain-Containing Phosphatase 2. In: Hayat, M. (eds) Tumor Dormancy, Quiescence, and Senescence, Volume 1. Tumor Dormancy and Cellular Quiescence and Senescence, vol 1. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5958-9_21
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