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

Oncogene volume 30, pages 3813–3820 (2011)Cite this article

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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.

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Acknowledgements

We wish to thank Dr Angela Santoni for her continued support. We thank Dr de Franciscis and Dr Colucci D’Amato for providing DUSP6-MKP3 cDNA in the pSG5 vectors; Dr Furnari and Dr Cavenee for mutant EGFRvIII U87MG cells and Dr Ricci-Vitiani for primary cultures of glioblastomas. We especially thank Dr Johan Lennartson for the ‘home-made’ antibody anti-DUSP6/MKP3 and Dr Stephen Keyse for critical reading of the paper.

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Authors and Affiliations

  1. Department of Pathology, IRCCS Neuromed, Pozzilli, Italy

    S Messina & L Frati

  2. Department of Health and Motor Sciences, University of Cassino, Cassino, Italy

    S Messina

  3. Department of Experimental Chemotherapy, Regina Elena Cancer Institute, Rome, Italy

    C Leonetti

  4. Department of Health Sciences, University of Campobasso, Campobasso, Italy

    C Zuchegna & E Di Zazzo

  5. Department of Structural and Functional Biology, Federico II University of Naples, Naples, Italy

    C Zuchegna & A Porcellini

  6. Department of Medical and Surgical Sciences and Biotecnology, Sapienza University of Rome, Rome, Italy

    A Calogero

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Correspondence to S Messina or A Porcellini.

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Messina, S., Frati, L., Leonetti, C. et al. Dual-specificity phosphatase DUSP6 has tumor-promoting properties in human glioblastomas. Oncogene 30, 3813–3820 (2011). https://doi.org/10.1038/onc.2011.99

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