The cytoplasmic part of L1-CAM controls growth and gene expression in human tumors that is reversed by therapeutic antibodies

被引:72
作者
Gast, D. [1 ]
Riedle, S. [1 ]
Issa, Y. [1 ]
Pfeifer, M. [1 ]
Beckhove, P. [1 ]
Sanderson, M. P. [1 ]
Arlt, M. [2 ]
Moldenhauer, G. [1 ]
Fogel, M. [3 ]
Krueger, A. [2 ]
Altevogt, P. [1 ]
机构
[1] German Canc Res Ctr, Tumor Immunol Programme, D-69120 Heidelberg, Germany
[2] Tech Univ Munich, Inst Expt Oncol & Therapy, Munich, Germany
[3] Kaplan Med Ctr, Dept Pathol, Rehovot, Israel
关键词
cell migration; tumor growth; signaling; therapeutic antibodies;
D O I
10.1038/sj.onc.1210747
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
L1 cell adhesion molecule (L1-CAM) is a transmembrane cell adhesion molecule involved in cell migration and axon guidance in the developing nervous system. L1 is also overexpressed in ovarian and endometrial carcinomas and is associated with a bad prognosis. In carcinoma cell lines, L1 overexpression augments cell motility, tumor growth in mice and induces expression of Erk-dependent genes. Here, we show that a mutation in the cytoplasmic portion of L1 (T1247A, S1248A) abrogates Erk activation, blocks cell migration on extracellular matrix proteins and did not augment tumor growth in non-obese diabetic/severe combined immuno-deficient mice. In cells expressing mutant L1, the induction of Erk-dependent genes such as beta 3-integrin, cathepsin-B and several transcription factors is eliminated and the invasive phenotype is abrogated. L1 antibodies showed similar effects. They prevented Erk activation and interfered with the Erk-dependent gene expression pattern. These findings provide a rationale for the mode of action of L1 antibodies and suggest that interference with L1 function could become a valuable target for therapy.
引用
收藏
页码:1281 / 1289
页数:9
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