title: Adenoviral transgene expression of MMAC/PTEN in human glioma cells inhibits Akt activation and induces anoikis.
abstract: The MMAC/PTEN tumor suppressor gene encodes for a phosphatase that recently has been shown to have phosphotidylinositol phosphatase activity, implicating its possible involvement in phosphatidylinositol 3'-kinase-mediated signaling. To investigate possible alterations in growth factor-mediated signal transduction, an adenovirus containing MMAC/PTEN, Ad-MMAC, previously shown to inhibit growth and tumorigenicity in glioma cells, was used to acutely express the transgene. Human glioma cells infected with Ad-MMAC but not with control adenoviruses exhibited an inhibition of phosphorylation of both activating residues of Akt, Ser-473, and Thr-308, along with Akt's serine/threonine kinase activity, without significantly altering Akt expression. The effects of functional MMAC/PTEN expression were relatively specific, because members of several other growth factor-mediated signaling pathways showed no altered responses. The presence of MMAC/PTEN also inhibited phosphorylation of BAD, although no evidence of apoptosis in the in situ treated cells was observed. However, U251 glioma cells infected with Ad-MMAC were induced to undergo anoikis at a significantly higher rate than U251 cels treated with control viruses or mock infected with media. These results demonstrate that the acute administration of MMAC/PTEN results in the inhibition of Akt-mediated signaling, growth inhibition, and anoikis, implying that loss of MMAC/PTEN increases cellular proliferation and significantly augments a cell's survival potential during cellular processes that are associated with malignancy.
authors.affiliation: Department of Neuro-Oncology and The Brain Tumor Center, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Davies
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.forename: T
authors.initials: T
authors.lastname: Sano
authors.forename: X
authors.initials: X
authors.lastname: Fang
authors.forename: P
authors.initials: P
authors.lastname: Tang
authors.forename: R
authors.initials: R
authors.lastname: LaPushin
authors.forename: D
authors.initials: D
authors.lastname: Koul
authors.forename: R
authors.initials: R
authors.lastname: Bookstein
authors.forename: D
authors.initials: D
authors.lastname: Stokoe
authors.forename: W K
authors.initials: WK
authors.lastname: Yung
authors.forename: G B
authors.initials: GB
authors.lastname: Mills
authors.forename: P A
authors.initials: PA
authors.lastname: Steck
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000096:biosynthesis / Q000502:physiology; D015870:Gene Expression; D016147:Genes, Tumor Suppressor; D005909:Glioblastoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000502:physiology; D019076:Transgenes; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
chemical_list: D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D066246:ErbB Receptors; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human