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J. Biol. Chem., Vol. 281, Issue 36, 26350-26360, September 8, 2006

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Cytocidal Actions of Parasporin-2, an Anti-tumor Crystal Toxin from Bacillus thuringiensis^*

Sakae Kitada¹², Yuichi Abe¹, Hiroyasu Shimada, Yoshitomo Kusaka, Yoko Matsuo, Hideki Katayama, Shiro Okumura, Tetsuyuki Akao, Eiichi Mizuki, Osamu Kuge, Yasuyuki Sasaguri^¶, Michio Ohba^||, and Akio Ito

From the Department of Chemistry, Faculty of Science, Kyushu University, Fukuoka 812-8581, Biotechnology and Food Research Institute, Fukuoka Industrial Technology Center, Fukuoka 839-0861, the ^¶Department of Pathology and Cell Biology, University of Occupational and Environmental Health, Fukuoka 807-8555, and the ^||Department of Applied Genetics and Pest Management, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581, Japan

Parasporin-2, a new crystal protein derived from noninsecticidal and nonhemolytic Bacillus thuringiensis, recognizes and kills human liver and colon cancer cells as well as some classes of human cultured cells. Here we report that a potent proteinase K-resistant parasporin-2 toxin shows specific binding to and a variety of cytocidal effects against human hepatocyte cancer cells. Cleavage of the N-terminal region of parasporin-2 was essential for the toxin activity, whereas C-terminal digestion was required for rapid cell injury. Protease-activated parasporin-2 induced remarkable morphological alterations, cell blebbing, cytoskeletal alterations, and mitochondrial and endoplasmic reticulum fragmentation. The plasma membrane permeability was increased immediately after the toxin treatment and most of the cytoplasmic proteins leaked from the cells, whereas mitochondrial and endoplasmic reticulum proteins remained in the intoxicated cells. Parasporin-2 selectively bound to cancer cells in slices of liver tumor tissues and susceptible human cultured cells and became localized in the plasma membrane until the cells were damaged. Thus, parasporin-2 acts as a cytolysin that permeabilizes the plasma membrane with target cell specificity and subsequently induces cell decay.

Received for publication, March 20, 2006 , and in revised form, June 29, 2006.

^* This work was supported in part by Grants-in-aid for Scientific Research 16770077 and 17053019 (to S. K.) and Special Coordination Funds for the Promotion of Science and Technology from the Ministry of Education, Science, Sports and Culture of the Japanese Government. 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 Fig. 1.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 81-92-642-4182; Fax: 81-92-642-2607; E-mail: s.kitscc{at}mbox.nc.kyushu-u.ac.jp.

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