Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

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

Oncogene volume 22, pages 2655–2663 (2003)Cite this article

Abstract

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 (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 pan-caspase 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 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 ΔN Bax may provide a better alternative than currently used cytotoxic genes in cancer gene therapy trials.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Ambrosini G, Adida C and Altieri DC . (1997). Nat. Med., 3, 917–921.

  • Aritomi M, Kunishima N, Inohara N, Ishibashi Y, Ohta S and Morikawa K . (1997). J. Biol. Chem., 272, 27886–27892.

  • Asoh S, Nishimaki K, Nanbu-Wakao R and Ohta S . (1998). J. Biol. Chem., 273, 11384–11391.

  • Beck WT and Dalton WS . (1997). In: Caner: Principles and Practice of Oncology. 5th edn. Devita JVT, Hellman S, Rosenberg SA (eds.). Lippincott-Raven Publishers: Philadelphia, NY, pp. 333–348.

    Google Scholar 

  • Costantini P, Jacotot E, Decaudin D and Kroemer G . (2000). J. Natl. Cancer. Inst., 92, 1042–1053.

  • Cregan SP, Fortin A, MacLaurin JG, Callaghan SM, Cecconi F, Yu SW, Dawson TM, Dawson VL, Park DS, Kroemer G and Slack RS . (2002). J. Cell Biol., 158, 507–517.

  • Eekes R, Antonsson B, Osen-Sand A, Montessuit S, Richter C, Sadoul R, Mazzei G, Nichols A and Martinou JC . (1998) J. Cell. Biol., 143, 217–224.

  • Fan L, Freeman KW, Khan T, Pham E and Spencer DM . (1999). Hum. Gene Ther., 10, 2273–2285.

  • Finucane DM, Bossy-Wetzel E, Waterhouse NJ, Cotter TG and Green DR . (1999). J. Biol. Chem., 274, 2225–2233.

  • Green DR and Reed JC . (1998). Science, 281, 1309–1312.

  • Gross A, Jocker J, Wei MC and Korsmeyer SJ . (1998). EMBO J., 17, 3878–3885.

  • Gross A, Mcdonnel JM and Korsmeyer SJ . (1999). Genes. Dev., 13, 1899–1911.

  • Gu J, Andreeff M, Roth JA and Fang B . (2002). Gene Ther., 9, 30–37.

  • Gu J, Kagawa S, Takakura M, Kyo S, Inoue M, Roth JA and Fang B . (2000). Cancer Res., 60, 5359–5364.

  • Herr I and Debatin K-M . (2001). Blood, 98, 2603–2614.

  • Huang Z . (2000). Oncogene, 19, 6627–6631.

  • Hunter JJ and Parslow TG . (1996). J. Biol. Chem., 271, 8521–8524.

  • Igney FH and Krammer PH (2002). Nat. Rev. Cancer, 2, 277–288.

  • Ikegaki K, Katsumata M and Tsujimoto Y . (1994). Cancer Res., 54, 6–8.

  • Ishibashi Y, Nishimaki K, Asoh S, Nanbu-Wakao R, Yamada T and Ohta S . (1998). Biochem. Biophys. Res. Commum., 243, 609–616.

  • Joseph B, Marchetti P, Formstecher P, Kroemer G, Lewensohn R and Zhivotovsky B . (2002). Oncogene, 21, 65–77.

  • Jurgensmeier JM, Krajewski S, Armstrong RC, Wilson GM, Oltersdorf T, Fritz CC, Reed JC and Ottilie S . (1997). Mol. Biol. Cell., 8, 325–339.

  • Kagawa S, Gu J, Swisher SG, Ji L, Roth JA, Lai D, Stephens C and Fang B . (2000a). Cancer Res., 60, 1157–1161.

  • Kagawa S, Pearson SA, Ji L, Xu K, McDonnell TJ,, Swisher SG, Roth JA and Fang B . (2000b). Gene Ther., 7, 75–79.

  • Kanegae Y, Lee G, Sato Y, Tanaka M, Nakai M, Sasaki T, Sugano S and Saito I . (1995). Nucleic Acids Res., 23, 3816–3321.

  • Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES and Wang X . (1997). Cell, 91, 479–489.

  • Li X, Marani M, Yu J, Nan B, Roth JA, K S, Fang B, Denner L and Marcelli M . (2001). Cancer Res., 61, 186–191.

  • McCormick F . (2001). Nat. Rev. Cancer, 1, 130–140.

  • Mohiuddin I, Cao X, Fang B, Nishizaki M and Smythe WR . (2001). Cancer Gene Ther., 8, 547–554.

  • Muchmore SW, Sattler M, Liang H, Meadows RP, Harlan JE, Yoon HS, Nettesheim D, Chang BS, Thompson CB, Wong SL, Ng SL and Fesik SW . (1996). Nature, 381, 335–341.

  • Oltvai ZN, Milliman CL and Korsmeyer SJ . (1993). Cell, 74, 609–619.

  • Pastorino JG, Chen ST, Tafani M, Snyder JW and Farber JL . (1998). J. Biol. Chem., 273, 7770–7775.

  • Pezzella F, Turley H, Kuzu, Tungekar MF, Dunnill MS, Pierce CB, Harris A, Gatter KC and Mason DY . (1993). N. Eng. J. Med., 329, 690–694.

  • Sperandio S, Belle I and Bredesen DE . (2000). Proc. Natl. Acad. Sci. USA, 97, 14376–14381.

  • Suzuki M, Youle RJ and Tjandra N . (2000). Cell, 103, 645–654.

  • Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett D, Aebersold R, Siderovski DP, Penninger JM and Kroemer G . (1999). Nature, 397, 441–446.

  • Tai Y-T, Strobel T, Kufe D and Cannistra SA . (1999). Cancer Res., 59, 2121–2126.

  • Takahashi T, Nau MM, Chiba I, Birrer MJ, Rosenberg RK, Vinocour M, Levitt M, Pass H, Gazdar AF and Minna JD . (1989). Science, 246, 491–494.

  • Takimoto R and El-DeiryL WS . (2000). Oncogene, 19, 1735–1743.

  • Tamm I, Wang Y, Sausville E, Scudiero DA, Vigna N, Oltersdorf T and Reed JC . (1998). Cancer Res., 58, 5315–5320.

  • Wang K, Gross A, Waksman G and Korsmeyer SJ . (1998). Mol. Cell. Biol., 18, 6083–6089.

  • Wu CH, Gordon J, Rastegar M, Ogretmen B and Safa AR . (2002) Oncogene, 21, 5160–5174.

  • Xiang J, Chao DT and Korsmeyer SJ . (1996). Proc. Natl. Acad. Sci. USA, 93, 14559–14563.

  • Yamashita Y, Shimada M, Tanaka S, Okamoto M, Miyazaki J and Sugimachi K . (2002). Hum. Gene Ther., 13, 275–286.

  • Yin XM, Oltvai ZN and Korsmeyer SJ . (1994). Nature, 369, 321–323.

Download references

Author information

Authors and Affiliations

  1. Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer, Tohoku University, 4-1 Seiryomachi, Aobaku, 980-8575, Sendai, Japan

    Kazuhiro Usui, Yasuo Saijo, Ko Narumi, Shohei Koyama, Makoto Maemondo, Toshiaki Kikuchi, Ryushi Tazawa, Koichi Hagiwara & Toshihiro Nukiwa

  2. Department of Molecular Medicine and Gene Transfer Research, Tohoku University Graduate School of Medicine, 2-1 Seiryomachi, Aobaku, 980-8575, Sendai, Japan

    Yasuo Saijo

  3. Department of Biochemistry and Cell Biology, Institute of Gerontology, Nippon Medical School, 1-396 Kosugicho, Nakaharaku, 211-8533, Kawasaki, Japan

    Yoshitomo Ishibashi & Shigeo Ohta

Authors
  1. Kazuhiro Usui
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yasuo Saijo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ko Narumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shohei Koyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Makoto Maemondo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Toshiaki Kikuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ryushi Tazawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Koichi Hagiwara
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yoshitomo Ishibashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shigeo Ohta
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Toshihiro Nukiwa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yasuo Saijo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Usui, K., Saijo, Y., Narumi, K. et al. N-terminal deletion augments the cell-death-inducing activity of BAX in adenoviral gene delivery to nonsmall cell lung cancers. Oncogene 22, 2655–2663 (2003). https://doi.org/10.1038/sj.onc.1206331

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206331

Keywords

This article is cited by

Search

Advanced search

Quick links