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. 2000 Jan;91(1):41–51. doi: 10.1111/j.1349-7006.2000.tb00858.x

Adenovirus‐mediated Gene Transduction of IkB or IkB Plus Bax Gene Drastically Enhances Tumor Necrosis Factor (TNF)‐induced Apoptosis in Human Gliomas

Nobusada Shinoura 1,2, Naoki Yamamoto 1, Yoko Yoshida 1, Takashi Fujita 3, Nobuto Saito 2, Akio Asai 2, Takaaki Kirino 2,4, Hirofumi Hamada 1,5,✉
PMCID: PMC5926230  PMID: 10744043

Abstract

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.

Keywords: Apoptosis, IkB, TNF, Bax, Gene therapy

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