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J. Biol. Chem., Vol. 281, Issue 19, 13620-13627, May 12, 2006

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Molecular Cloning and Functional Characterization of a Cell-permeable Superoxide Dismutase Targeted to Lung Adenocarcinoma Cells

INHIBITION CELL PROLIFERATION THROUGH THE Akt/p27^kip1 PATHWAY^*

Min Lu, Xingguo Gong¹, Yuwen Lu, Jianjun Guo, Chenhui Wang, and Yuanjiang Pan²

From the Institute of Biochemistry, Zhejiang University, Hangzhou, 310027, China and the Institute of Chemical Biology and Pharmaceutical Chemistry, Zhejiang University, Hangzhou, 310027, China

In clinical oncology, many trials with superoxide dismutase (SOD) have failed to demonstrate antitumor ability and in many cases even caused deleterious effects because of low tumor-targeting ability. In the current research, the Nostoc commune Fe-SOD coding sequence was amplified from genomic DNA. In addition, the single chain variable fragment (ScFv) was constructed from the cDNA of an LC-1 hybridoma cell line secreting anti-lung adenocarcinoma monoclonal antibody. After modification, the SOD and ScFv were fused and co-expressed, and the resulting fusion protein produced SOD and LC-1 antibody activity. Tracing SOD-ScFv by fluorescein isothiocyanate and superoxide anions () in SPC-A-1 cells showed that the fusion protein could recognize and enter SPC-A-1 cells to eliminate . The lower oxidative stress resulting from the decrease in cellular delayed the cell cycle at G₁ and significantly slowed SPC-A-1 cell growth in association with the dephosphorylation of the serine-threonine protein kinase Akt and expression of p27^kip1. The tumor-targeting fusion protein resulting from this research overcomes two disadvantages of SODs previously used in the clinical setting, the inability to target tumor cells or permeate the cell membrane. These findings lay the groundwork for development of an efficient antitumor drug targeted by the ScFv.

Received for publication, January 18, 2006 , and in revised form, March 15, 2006.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY830114 [GenBank] .

^* This work was supported by a grant from the National Innovation Fund for Technology, the Ministry of Science and Technology of China (Number 03C26213300586). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental material.

¹ To whom correspondence may be addressed: Institute of Biochemistry, Zhejiang University, Qiushi road 38#, Hangzhou, China. Tel./Fax: 86-571-87953002; E-mail: gongxg{at}zju.edu.cn. ² To whom correspondence may be addressed: Institute of Chemical Biology and Pharmaceutical Chemistry, Zhejiang University, Qiushi road 38#, Hangzhou, China. Tel./Fax: 86-571-87951264; E-mail: panyuanjiang{at}zju.edu.cn.

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