Dual-specificity phosphatase DUSP6 has tumor-promoting properties in human glioblastomas

Abstract

Dual-specificity phosphatase 6 (DUSP6, mitogen-activated protein kinase (MAPK) phosphatase 3 or PYST1) dephosphorylates phosphotyrosine and phosphothreonine residues on extracellular signal-regulated kinase (ERK1/ 2; MAPK1/2) to inactivate the ERK1/2 kinase. DUSP6 is a critical regulator of the ERK signaling cascade and has been implicated as a tumor suppressor. We report here experimental evidences that DUSP6 is transcriptionally upregulated in primary and long-term cultures of human glioblastoma, as assayed by northern hybridization and real-time quantitative PCR, producing constitutive high level of protein expression. Functional assays were performed with adenovirus-mediated expression of DUSP6 in glioblastoma cultures. Protein overexpression inhibits growth by inducing G1-phase delay and increased mitogenic/anchorage dependence and clonogenic potential in vitro. Changes in cell morphology were associated with an increased tumor growth in vivo. Chemoresistance is a major cause of treatment failure and poor outcome in human glioblastomas. Importantly, DUSP6 overexpression increased resistance to cisplatinmediated cell death in vitro and in vivo. Antisense-mediated depletion of DUSP6 acted in lowering the threshold to anticancer DNA-damaging drugs. We conclude that upregulation of DUSP6 exerts a tumor-promoting role in human glioblastomas exacerbating the malignant phenotype.

DUSP6/MKP3 is overexpressed in papillary and poorly differentiated thyroid carcinoma and contributes to neoplastic properties of thyroid cancer cells

“…Quyun et al 2010). In addition, a tumour-promoting role for DUSP6 has recently been suggested in glioblastoma cells (Messina et al 2011).…”

“…By contrast, DUSP6 is upregulated in myeloma cell lines with an active NRAS mutation, melanoma cell lines with BRAF or NRAS mutations, colon carcinoma and ERBB2-positive breast cancers (Croonquist et al 2003, Bloethner et al 2005, Lucci et al 2010, Quyun et al 2010. In addition, DUSP6 pro-survival functions have been hypothesised in HeLa (MacKeigan et al 2005) and breast cancer cells (Lonne et al 2009), and a tumour-promoting role has recently been suggested in glioblastoma cells (Messina et al 2011).…”

Caspase-3 Cleavage of DUSP6/MKP3 at the Interdomain Region Generates Active MKP3 Fragments That Regulate ERK1/2 Subcellular Localization and Function

“…Interestingly, a putative MKP3 isoform lacking the interdomain linker region has been found in pancreatic cancer and glioblastoma samples, although its function remains unknown. 52,53 The MKP3-related, ERK1/2-specific DUSP7/MKPX and DUSP9/MKP4 proteins share with MKP3 the presence of conserved putative caspase-3 target residues in their interdomain linker regions. Noticeably, DUSP9/MKP4 lacks the N-terminal caspase-3 cleavage site (Asp152 in MKP3 and Asp191 in DUSP7/MKPX) (Fig.…”

Cancer adjuvant chemotherapy strategic classification by artificial neural network with gene expression data: An example for non-small cell lung cancer

“…LCK is a member of the Src family of protein tyrosine kinases (PTKs) and is a key signaling molecule in the selection and maturation of developing T-cells [27][28][29]. Several studies have indicated the DUSP6 function in regulating genomic integrity and sensitivity to chemotherapy in cancer [30][31][32][33]. Overexpression of DUSP6 was promotes tumor development to cause refractory to chemotherapy [32].…”

“…Several studies have indicated the DUSP6 function in regulating genomic integrity and sensitivity to chemotherapy in cancer [30][31][32][33]. Overexpression of DUSP6 was promotes tumor development to cause refractory to chemotherapy [32]. LCK is linked to higher resistance to platinum complexes and other chemotherapeutics [34].…”