Mechanisms for the apoptosis of small cell lung cancer cells induced by anti-GD2 monoclonal antibodies: roles of anoikis.
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.
Aixinjueluo
Wei
W
Department of Biochemistry II and Oral and Maxillofacial Surgery, Nagoya University School of Medicine 65 Tsurumai, Showa-ku, Japan.
Furukawa
Keiko
K
Zhang
Qing
Q
Hamamura
Kazunori
K
Tokuda
Noriyo
N
Yoshida
Shoko
S
Ueda
Ryuzo
R
Furukawa
Koichi
K
D023102:Anoikis / Q000502:physiology*; D000911:Antibodies, Monoclonal / Q000276:immunology*; D017209:Apoptosis; D018288:Carcinoma, Small Cell / Q000473:pathology*; D045744:Cell Line, Tumor; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005732:Gangliosides / Q000032:analysis / Q000276:immunology / Q000502:physiology*; D006801:Humans; D016023:Integrins / Q000502:physiology; D008175:Lung Neoplasms / Q000473:pathology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000911:Antibodies, Monoclonal; D005732:Gangliosides; D016023:Integrins; C019403:ganglioside, GD2; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases