title: Regulation of GST-MDA-7 toxicity in human glioblastoma cells by ERBB1, ERK1/2, PI3K, and JNK1-3 pathway signaling.
abstract: The present studies defined the biological effects of a GST fusion protein of melanoma differentiation-associated gene-7 (mda-7), GST-MDA-7 (1 and 30 nmol/L), on cell survival and cell signaling in primary human glioma cells in vitro. GST-MDA-7, in a dose- and time-dependent fashion killed glioma cells with diverse genetic characteristics; 1 nmol/L caused arrest without death, whereas 30 nmol/L caused arrest and killing after exposure. Combined inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT function was required to enhance 1 nmol/L GST-MDA-7 lethality in all cell types, whereas combined activation of MEK1 and AKT was required to suppress 30 nmol/L GST-MDA-7 lethality; both effects are mediated in part by modulating c-Jun NH(2)-terminal kinase (JNK) 1-3 activity. The geldanamycin 17AAG inhibited AKT and ERK1/2 in GBM cells and enhanced GST-MDA-7 lethality. JNK1-3 signaling promoted BAX activation and mitochondrial dysfunction. In GBM6 cells, GST-MDA-7 (30 nmol/L) transiently activated p38 mitogen-activated protein kinase, which was modestly protective against JNK1-3-induced toxicity, whereas GST-MDA-7 (300 nmol/L) caused prolonged intense p38 mitogen-activated protein kinase activation, which promoted cell death. In GBM12 cells that express full-length mutant activated ERBB1, inhibition of ERBB1 did not modify GST-MDA-7 lethality; however, in U118 established glioma cells, stable overexpression of wild-type ERBB1 and/or truncated active ERBB1vIII suppressed GST-MDA-7 lethality. Our data argue that combined inhibition of ERK1/2 and AKT function, regardless of genetic background, promotes MDA-7 lethality in human primary human glioma cells via JNK1-3 signaling and is likely to represent a more ubiquitous approach to enhancing MDA-7 toxicity in this cell type than inhibition of ERBB1 function.
authors.affiliation: Department of Biochemistry, Virginia Commonwealth University, Richmond, VA 23298-0035, USA.
authors.forename: Adly
authors.initials: A
authors.lastname: Yacoub
authors.forename: Pankaj
authors.initials: P
authors.lastname: Gupta
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Park
authors.forename: Mohammed
authors.initials: M
authors.lastname: Rhamani
authors.forename: Hossein
authors.initials: H
authors.lastname: Hamed
authors.forename: David
authors.initials: D
authors.lastname: Hanna
authors.forename: Guo
authors.initials: G
authors.lastname: Zhang
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Irina V
authors.initials: IV
authors.lastname: Lebedeva
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.forename: Costas
authors.initials: C
authors.lastname: Koumenis
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D002470:Cell Survival; D003603:Cytotoxins / Q000235:genetics / Q000494:pharmacology; D066246:ErbB Receptors / Q000502:physiology*; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology*; D005982:Glutathione Transferase / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D007378:Interleukins / Q000235:genetics* / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048057:Mitogen-Activated Protein Kinase 10 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D048055:Mitogen-Activated Protein Kinase 8 / Q000502:physiology; D048056:Mitogen-Activated Protein Kinase 9 / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors; D014407:Tumor Cells, Cultured; D000099180:Interleukin-24
chemical_list: D003603:Cytotoxins; D066246:ErbB Receptors; D005982:Glutathione Transferase; D007378:Interleukins; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048057:Mitogen-Activated Protein Kinase 10; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D019869:Phosphatidylinositol 3-Kinases; D011993:Recombinant Fusion Proteins; D000099180:Interleukin-24