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ICAM-2 confers a non-metastatic phenotype in neuroblastoma cells by interaction with ?-actinin.


ABSTRACT: Progressive metastatic disease is a major cause of mortality for patients diagnosed with multiple types of solid tumors. One of the long-term goals of our laboratory is to identify  molecular interactions that regulate metastasis, as a basis for developing agents that inhibit this process. Toward this goal, we recently demonstrated that intercellular adhesion molecule-2 (ICAM-2) converted neuroblastoma (NB) cells from a metastatic to a non-metastatic phenotype, a previously unknown function for ICAM-2. Interestingly, ICAM-2 suppressed metastatic but not tumorigenic potential in preclinical models, supporting a novel mechanism of regulating metastasis. We hypothesized that the effects of ICAM-2 on NB cell phenotype depend on the interaction of ICAM-2 with the cytoskeletal linker protein ?-actinin. The goal of the study presented here was to evaluate the impact of ?-actinin binding to ICAM-2 on the phenotype of NB tumor cells. We used in silico approaches to examine the likelihood that the cytoplasmic domain of ICAM-2 binds directly to ?-actinin. We then expressed variants of ICAM-2 with mutated ?-actinin-binding domains, and compared the impact of ICAM-2 and each variant on NB cell adhesion, migration, anchorage-independent growth, co-precipitation with ?-actinin and production of localized and disseminated tumors in vivo. The in vitro and in vivo characteristics of cells expressing ICAM-2 variants with modified ?-actinin-binding domains differed from cells expressing ICAM-2 wild type (WT) and also from cells that expressed no detectable ICAM-2. Like the WT protein, ICAM-2 variants inhibited cell adhesion, migration and colony growth in vitro. However, unlike the WT protein, ICAM-2 variants did not completely suppress development of disseminated NB tumors in vivo. The data suggest the presence of ?-actinin-dependent and ?-actinin-independent mechanisms, and indicate that the interaction of ICAM-2 with ?-actinin is critical to conferring an ICAM-2-mediated non-metastatic phenotype in NB cells.

SUBMITTER: Feduska JM 

PROVIDER: S-EPMC6746311 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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ICAM-2 confers a non-metastatic phenotype in neuroblastoma cells by interaction with α-actinin.

Feduska J M JM   Aller S G SG   Garcia P L PL   Cramer S L SL   Council L N LN   van Waardenburg R C A M RC   Yoon K J KJ  

Oncogene 20140407 12


Progressive metastatic disease is a major cause of mortality for patients diagnosed with multiple types of solid tumors. One of the long-term goals of our laboratory is to identify  molecular interactions that regulate metastasis, as a basis for developing agents that inhibit this process. Toward this goal, we recently demonstrated that intercellular adhesion molecule-2 (ICAM-2) converted neuroblastoma (NB) cells from a metastatic to a non-metastatic phenotype, a previously unknown function for  ...[more]

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