Mechanisms for the apoptosis of small cell lung cancer cells induced by anti-GD2 monoclonal antibodies: roles of anoikis.

Abstract

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.

• Authors: Wei Aixinjueluo, Keiko Furukawa, Qing Zhang, Kazunori Hamamura, Noriyo Tokuda, Shoko Yoshida, Ryuzo Ueda, Koichi Furukawa
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 280 Issue 33 Pg. 29828-36 (Aug 19 2005) ISSN: 0021-9258 [Print] United States
• PMID: 15923178 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Gangliosides
• Integrins
• ganglioside, GD2
• Protein-Tyrosine Kinases
• Focal Adhesion Kinase 1
• Focal Adhesion Protein-Tyrosine Kinases
• PTK2 protein, human
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases

Topics

• Anoikis (physiology)
• Antibodies, Monoclonal (immunology)
• Apoptosis
• Carcinoma, Small Cell (pathology)
• Cell Line, Tumor
• Focal Adhesion Kinase 1
• Focal Adhesion Protein-Tyrosine Kinases
• Gangliosides (analysis, immunology, physiology)
• Humans
• Integrins (physiology)
• Lung Neoplasms (pathology)
• Mitogen-Activated Protein Kinases (metabolism)
• Phosphorylation
• Protein-Tyrosine Kinases (physiology)
• p38 Mitogen-Activated Protein Kinases (metabolism)