N-terminal deletion augments the cell-death-inducing activity of BAX in adenoviral gene delivery to nonsmall cell lung cancers.
Therapeutic modalities that overcome the antiapoptotic function of Bcl-2 that is often overexpressed in cancer cells are expected to be a novel strategy for cancer treatment. We previously reported that the leukemic cell death induced by an N-terminally truncated Bax (deltaN Bax: corresponding to amino acid 112-192 of full-length Bax) was not blocked by Bcl-2 or Bcl-x(L) 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 deltaN Bax, and investigated the effects of the deltaN Bax gene transfer into A549 and NCI-H1299 nonsmall cell lung cancer cell lines. deltaN Bax showed more cell-death-inducing activity in both cells than did the full-length Bax in vitro. It was found that the deltaN Bax-induced cell death was not inhibited by the pan-caspase inhibitor z-VAD-fmk, suggesting that deltaN Bax induces cell death through a caspase-independent mechanism. Intratumoral injection of adenoviruses expressing deltaN Bax into A549 tumors in Balb/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 deltaN Bax may provide a better alternative than currently used cytotoxic genes in cancer gene therapy trials.
Usui
Kazuhiro
K
Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer, Tohoku University, 4-1 Seiryomachi, Aobaku, Sendai 980-8575, Japan.
Saijo
Yasuo
Y
Narumi
Ko
K
Koyama
Shohei
S
Maemondo
Makoto
M
Kikuchi
Toshiaki
T
Tazawa
Ryushi
R
Hagiwara
Koichi
K
Ishibashi
Yoshitomo
Y
Ohta
Shigeo
S
Nukiwa
Toshihiro
T
D000256:Adenoviridae; D017209:Apoptosis / Q000502:physiology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000628:therapy*; D005822:Genetic Vectors; D006801:Humans; D066298:In Vitro Techniques; D008175:Lung Neoplasms; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D017384:Sequence Deletion; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein