Open AccessAdenovirus‐mediated Gene Transduction of IkB or IkB Plus Bax Gene Drastically Enhances Tumor Necrosis Factor (TNF)‐induced Apoptosis in Human Gliomas
Author(s) -
Shinoura Nobusada,
Yamamoto Naoki,
Yoshida Yoko,
Fujita Takashi,
Saito Nobuto,
Asai Akio,
Kirino Takaaki,
Hamada Hirofumi
Publication year - 2000
Publication title -
japanese journal of cancer research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 0910-5050
DOI - 10.1111/j.1349-7006.2000.tb00858.x
Subject(s) - tumor necrosis factor alpha , apoptosis , transduction (biophysics) , genetic enhancement , cancer research , cell culture , signal transduction , biology , microbiology and biotechnology , nfkb1 , programmed cell death , cancer cell , gene , cancer , immunology , biochemistry , transcription factor , genetics
Tumor necrosis factor‐α (TNF), which was initially supposed to be a promising cancer therapeutic reagent, does not kill most types of cancer cells partly due to the activation of an anti‐apoptotic gene, NF‐kB. NF‐kB forms an inactive complex with the inhibitor kappa B alpha (IkBα), which is rapidly phosphorylated and degraded in response to various extracellular signals. To disrupt this protective mechanism, we introduced an inhibitor kappa B alpha (IkBdN) gene, a deletion mutant gene lacking the nucleotides for the N‐terminal 36 amino acids of IkBα, into human glioma cells (U251, T‐98G, and U‐373MG) via an adenoviral (Adv) vector in addition to treatment of the glioma cells with recombinant TNF. Immunohistochemical analysis revealed that NF‐kB was translocated to nuclei by TNF treatment in U251 and T‐98G cells, but not in U‐373MG cells. Neither transduction of IkBdN nor treatment with TNF protein alone induced apoptosis in U251 and T‐98G cells, whereas both cell lines underwent drastic TNF‐induced apoptosis after transduction of IkBdN. On the other hand, U‐373MG cells were refractory to TNF‐induced apoptosis even when they were transduced with the IkBdN gene. U‐373MG cells underwent drastically increased apoptosis when co‐transduced with the IkBdN and Bax gene in the presence of TNF. Adv‐mediated transfer of IkBdN or IkBdN plus Bax may be a promising therapeutic approach to treat gliomas through TNF‐mediated apoptosis.