Targeting DUSPs in glioblastomas – wielding a double‐edged sword?

Abstract

Several dual-specificity phosphatases (DUSPs) that play key roles in the direct or indirect inactivation of different MAP kinases (MAPKs) have been implicated in human cancers over the past decade. This has led to a growing interest in identifying DUSPs and their specific inhibitors for further testing and validation as therapeutic targets in human cancers. However, the lack of understanding of the complex regulatory mechanisms and cross-talks between MAPK signaling pathways, combined with the fact that DUSPs can act as a double-edged sword in cancer progression, calls for a more careful and thorough investigation. Among the various types of brain cancer, glioblastoma multiforme (GBM) is notorious for its aggressiveness and resistance to current treatment modalities. This has led to the search for new molecular targets, particularly those involving various signaling pathways. DUSPs appear to be a promising target, but much more information on DUSP targets and their effects on GBM is needed before potential therapies can be developed, tested, and validated. This review identifies and summarize the specific roles of DUSP1, DUSP4, DUSP6 and DUSP26 that have been implicated in GBM.

Imbalanced signal transduction in regulatory T cells expressing the transcription factor FoxP3

“…Its best recognized substrate is pERK (39,40), although the full breadth of its substrates is not well charted. Dusp4 is strongly overexpressed in Treg cells, which might plausibly account for dampened TCR-induced signals in Treg cells.…”

Systematic screening of isogenic cancer cells identifies DUSP6 as context-specific synthetic lethal target in melanoma

“…HR: hazard ratio with 95% confidence interval. (D) Western blot analyses of siRNA-mediated DUSP6 knockdown in four selected melanoma cell lines with confirmed BRAF mutation status [43]. U: untreated; Ctrl: non-targeting control siRNA; siDu1 and siDu2: two DUSP6-targeting siRNAs.…”

“…The concept of TP53 gain-of-function mutants has been revitalized and the functions of oncogenic TP53 are currently under intensive investigation [39–41]. Importantly, members of the DUSP protein family, including DUSP6, have recently been proposed as therapeutic targets for glioblastoma multiforme, where DUSP6 causes tumor-promoting effects and chemoresistance [42, 43]. …”

DUSP26 (dual specificity phosphatase 26)

“…Gene amplifications, deletions and/or overexpression have been reported, and, among them, loss of the dual specificity phosphatase PTEN is a very common feature (Veliz et al, 2015). Dusp26 mRNA expression is also downregulated in human glioblastoma cell lines and in primary tumour samples and its downregulation was associated with invasive phenotypes (Patterson et al, 2010;Prabhakar et al, 2014;Tanuma et al, 2009;Vasudevan et al, 2005).It has been proposed that Dusp26 enhances cell-cell adhesion in GBM by promoting N-cadherin/Beta-catenin localization at the plasma membrane (Tanuma et al, 2009). The downregulation of Dusp26 mRNA has been observed also in ovarian cancer and medulloblastoma cell lines (Patterson et al, 2010) Disease Glioblastoma Multiforme (GBM)is a genetically heterogeneous group of brain tumours, which originates from glial cells (Urbanska et al, 2014).…”