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J. Biol. Chem., Vol. 280, Issue 33, 29828-29836, August 19, 2005

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Mechanisms for the Apoptosis of Small Cell Lung Cancer Cells Induced by Anti-GD2 Monoclonal Antibodies

ROLES OF ANOIKIS^*

Wei Aixinjueluo, Keiko Furukawa, Qing Zhang, Kazunori Hamamura, Noriyo Tokuda, Shoko Yoshida¶, Ryuzo Ueda¶, and Koichi Furukawa||

From the Departments of Biochemistry II and Oral and Maxillofacial Surgery, Nagoya University School of Medicine 65 Tsurumai, Showa-ku, Nagoya 466-0065, Japan and ^¶Department of Internal Medicine II, Nagoya City University School of Medicine, 1 Kawasumi, Mizuho-ku, Nagoya 467-8601, Japan

Anti-GD2 ganglioside antibodies could be a promising, novel therapeutic approach to the eradication of human small cell lung cancers, as anti-GD2 monoclonal antibodies (mAbs) induced apoptosis of small cell lung cancer cells in culture. In this study, we analyzed the mechanisms for the apoptosis of these cells by anti-GD2 mAbs and elucidated the mechanisms by which apoptosis signals were transduced via reduction in the phosphorylation levels of focal adhesion kinase (FAK) and the activation of a MAPK family member, p38, upon the antibody binding. Knock down of FAK resulted in apoptosis and p38 activation. The inhibition of p38 activity blocked antibody-induced apoptosis, indicating that p38 is involved in this process. Immunoprecipitation-immunoblotting analysis of immune precipitates with anti-FAK or anti-integrin antibodies using an anti-GD2 mAb revealed that GD2 could be precipitated with integrin and/or FAK. These results suggested that GD2, integrin, and FAK form a huge molecular complex across the plasma membrane. Taken together with the fact that GD2+ cells showed marked detachment from the plate during apoptosis, GD2+ small cell lung cancer cells seemed to undergo anoikis through the conformational changes of integrin molecules and subsequent FAK dephosphorylation.

Received for publication, December 14, 2004 , and in revised form, May 6, 2005.

^* This study was supported by the grants-in-aid for scientific research on priority areas from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT) (14082102, 16390075, 16590243). 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.

^|| To whom correspondence should be addressed: Dept. of Biochemistry II, Nagoya University School of Medicine 65 Tsurumai, Showa-ku, Nagoya 466-0065, Japan. Tel.: 81-52-744-2070; Fax: 81-52-744-2069; E-mail: koichi{at}med.nagoya-u.ac.jp.

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