N-terminal deletion augments the cell-death-inducing activity of BAX in adenoviral gene delivery to nonsmall cell lung cancers

Kazuhiro Usui, Yasuo Saijo, Ko Narumi, Shohei Koyama, Makoto Maemondo, Toshiaki Kikuchi, Ryushi Tazawa, Koichi Hagiwara, Yoshitomo Ishibashi, Shigeo Ohta, Toshihiro Nukiwa

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

Therapeutic modalities that overcome the antiapoptotic function of Bcl-2 that is often overexpressed in cancer cells are expected to he a novel strategy for cancer treatment. We previously reported that the leukemic cell death induced by an N-terminally truncated Bax (ΔN Bax: corresponding to amino acid 112-192 of full-length Bax) was not blocked by Bcl-2 or Bcl-XL owing to the lack of the BH3 domain needed to interact with the antiapoptotic Bcl-2 family molecules. In this study, we used the Cre-loxP system that allowed us to propagate adenoviruses expressing ΔN Bax, and investigated the effects of the ΔN Bax gene transfer into A549 and NCI-H1299 nonsmall cell lung cancer cell lines. ΔN Bax showed more cell-death-inducing activity in both cells than did the full-length Bax in vitro. It was found that the ΔN Bax-induced cell death was not inhibited by the pancaspase inhibitor z-VAD-fmk, suggesting that ΔN Bax induces cell death through a caspase-independent mechanism. Intratumoral injection of adenoviruses expressing ΔN Bax into A549 tumors in Balh/c nude mice showed a significantly stronger suppression of tumor growth (74%) than full-length Bax (25%) compared to the control. Our results suggest that ΔN Bax may provide a better alternative than currently used cytotoxic genes in cancer gene therapy trials.

Original languageEnglish
Pages (from-to)2655-2663
Number of pages9
JournalOncogene
Volume22
Issue number17
DOIs
Publication statusPublished - 2003 May 1

Keywords

  • Apoptosis
  • BAX
  • Gene therapy

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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