title: 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 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.
authors.affiliation: Department of Pathology, IRCCS Neuromed, Pozzilli, Italy. samantha.messina@uniroma1.it
authors.forename: S
authors.initials: S
authors.lastname: Messina
authors.forename: L
authors.initials: L
authors.lastname: Frati
authors.forename: C
authors.initials: C
authors.lastname: Leonetti
authors.forename: C
authors.initials: C
authors.lastname: Zuchegna
authors.forename: E
authors.initials: E
authors.lastname: Di Zazzo
authors.forename: A
authors.initials: A
authors.lastname: Calogero
authors.forename: A
authors.initials: A
authors.lastname: Porcellini
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D002460:Cell Line; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D051379:Mice; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6