title: Radiosensitization by inhibition of IkappaB-alpha phosphorylation in human glioma cells.
abstract: To assess the role of nuclear factor kappaB (NFKB) in cellular radiosensitivity, three different IkappaB-alpha (also known as NFKBIA) expression plasmids, i.e., S-IkappaB (mutations at (32, 36)Ser), Y-IkappaB (a mutation at (42)Tyr), and SY-IkappaB, were constructed and introduced into human brain tumor M054 cells. The clones were named as M054-S8, M054-Y2 and M054-SY4, respectively. Compared to the parental cell line, M054-S8 and M054-Y2 cells were more sensitive to X rays while M054-SY4 cells exhibited the greatest sensitivity. After treatment with N-acetyl-Leu-Leu-norleucinal, a proteasome inhibitor, the X-ray sensitivity of M054-S8 and M054-SY4 cells did not change, while that of M054-Y2 cells and the parental cells was enhanced. An increase in X-ray sensitivity accompanied by a decrease in translocation of NFKB to the nucleus in parental cells was observed after treatment with pervanadate, an inhibitor of tyrosine phosphatase, as well as in M054-S8 and M054-SY4 cells. Repair of potentially lethal damage (PLD) was observed in the parental cells but not in the clones. Four hours after irradiation (8 Gy), the expression of TP53 and phospho-p53 ((15)Ser) was induced in the parental cells but not in M054-S8, M054-Y2 or M054-SY4 cells. Our data suggest that inhibition of IkappaB-alpha phosphorylation at serine or tyrosine acts independently in sensitizing cells to X rays. NFKB may play a role in determining radiosensitivity and PLD repair in malignant glioma cells; TP53 may also be involved.
authors.affiliation: Department of Radiological Technology, School of Health Sciences, Faculty of Medicine, Hirosaki University, 66-1 Hon-cho, Hirosaki, 036-8564, Japan.
authors.forename: Gui-Rong
authors.initials: GR
authors.lastname: Ding
authors.forename: Naoko
authors.initials: N
authors.lastname: Honda
authors.forename: Takehisa
authors.initials: T
authors.lastname: Nakahara
authors.forename: Furong
authors.initials: F
authors.lastname: Tian
authors.forename: Masami
authors.initials: M
authors.lastname: Yoshida
authors.forename: Hideki
authors.initials: H
authors.lastname: Hirose
authors.forename: Junji
authors.initials: J
authors.lastname: Miyakoshi
mesh_terms: D002470:Cell Survival / Q000528:radiation effects; D003001:Cloning, Molecular; D004260:DNA Repair; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011836:Radiation Tolerance / Q000187:drug effects* / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D014638:Vanadates / Q000494:pharmacology
chemical_list: D007976:Leupeptins; D016328:NF-kappa B; C076715:pervanadate; C063261:acetylleucyl-leucyl-norleucinal; D014638:Vanadates