title: Down regulation of Akirin-2 increases chemosensitivity in human glioblastomas more efficiently than Twist-1.
abstract: The Twist-1 transcription factor and its interacting protein Akirin-2 regulate apoptosis. We found that in glioblastomas, highly malignant brain tumors, Akirin-2 and Twist-1 were expressed in glial fibrillary acidic protein positive tumor regions as well as in tumor endothelial cells and infiltrating macrophages / microglia. Temozolomide (TMZ) induced the expression of both molecules, partly shifting their nuclear to cytosolic localization. The knock-down (kd) of Akirin-2 increased the activity of cleaved (c)Caspase-3/-7, the amounts of cCaspases-3, -7 and cPARP-1 and resulted in an increased number of apoptotic cells after TMZ exposure. Glioblastoma cells containing decreased amounts of Akirin-2 after kd contained increased amounts of cCaspase-3 as determined by the ImageStreamx Mark II technology. For Twist-1, similar results were obtained with the exception that the combination of TMZ treatment and Twist-1 kd failed to significantly reduce chemoresistance compared with controls. This could be attributed to a cell population containing only slightly increased cCaspase-3 together with decreased Twist-1 levels, which was clearly larger than the respective population observed under Akirin-2 kd. Our results showed that, compared with Twist-1, Akirin-2 is the more promising target for RNAi strategies antagonizing Twist-1/Akirin-2 facilitated glioblastoma cell survival.
authors.affiliation: Institute of Zoology, Department of Structural Biology, 24118 Kiel, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Krossa
authors.affiliation: Department of Neurosurgery, University of Schleswig-Holstein Medical Center, 24105 Kiel, Germany.
authors.forename: Anne Dorothée
authors.initials: AD
authors.lastname: Schmitt
authors.affiliation: Department of Anatomy, University of Kiel, 24118 Kiel, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Hattermann
authors.affiliation: Institute of Immunology, University of Schleswig-Holstein Medical Center, 24105 Kiel, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Fritsch
authors.affiliation: Institute of Zoology, Department of Structural Biology, 24118 Kiel, Germany.
authors.forename: Axel J
authors.initials: AJ
authors.lastname: Scheidig
authors.affiliation: Department of Neurosurgery, University of Schleswig-Holstein Medical Center, 24105 Kiel, Germany.
authors.forename: Hubertus Maximilian
authors.initials: HM
authors.lastname: Mehdorn
authors.affiliation: Department of Neurosurgery, University of Schleswig-Holstein Medical Center, 24105 Kiel, Germany.
authors.forename: Janka
authors.initials: J
authors.lastname: Held-Feindt
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry; D017209:Apoptosis; D001932:Brain Neoplasms / Q000378:metabolism*; D039481:CD11b Antigen / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000737:chemistry; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005909:Glioblastoma / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008856:Microscopy, Fluorescence; D009687:Nuclear Proteins / Q000378:metabolism*; D034622:RNA Interference; D000077204:Temozolomide; D014157:Transcription Factors / Q000378:metabolism*; D051879:Twist-Related Protein 1 / Q000378:metabolism*; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D039481:CD11b Antigen; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; C509295:ITGAM protein, human; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; C485514:ZBTB7A protein, human; D014841:von Willebrand Factor; D003606:Dacarbazine; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D000077204:Temozolomide
keywords: Akirin-2; Twist-1; chemoresistance; glioblastoma