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

S. Messina, L. Frati, C. Leonetti, C. Zuchegna, E. Di Zazzo, A. Calogero, A. Porcellini

Research output: Contribution to journalArticle

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 cisplatin-mediated 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.

Original languageEnglish
Pages (from-to)3813-3820
Number of pages8
JournalOncogene
Volume30
Issue number35
DOIs
Publication statusPublished - Sep 1 2011

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Keywords

  • dual-specificity phosphatase
  • glioblastoma
  • tumor promoting

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Messina, S., Frati, L., Leonetti, C., Zuchegna, C., Di Zazzo, E., Calogero, A., & Porcellini, A. (2011). Dual-specificity phosphatase DUSP6 has tumor-promoting properties in human glioblastomas. Oncogene, 30(35), 3813-3820. https://doi.org/10.1038/onc.2011.99