ADAM23 Negatively Modulates αvβ3 Integrin Activation during Metastasis

Abstract

The ADAM23 gene is frequently silenced in different types of tumors, and, in breast tumors, silencing is correlated with tumor progression, suggesting that it might be associated with the acquisition of a metastatic phenotype. ADAM23 exerts its function mainly through the disintegrin domain, because its metalloprotease domain is inactive. Analysis of ADAM23 binding to integrins has revealed a specific interaction with A v B 3 integrin mediated by the disintegrin domain. Altered expression of A v B 3 integrin has been observed in different types of tumors, and expression of this integrin in the activated form has been shown to promote metastasis formation. Here, we investigated the possibility that interaction between ADAM23 and A v B 3 integrin might negatively modulate A v B 3 activation during metastatic progression. ADAM23 expression was knocked down using short hairpin RNA in the MDA-MB-435 cell line, which has been extensively used as a model for A v B 3 integrin activation. Ablation of ADAM23 enhanced A v B 3 integrin activation by at least 2-to 4-fold and ADAM23 knockdown cells showed enhanced migration and adhesion to classic A v B 3 integrin ligands. Ablation of ADAM23 expression also enhanced pulmonary tumor cell arrest in immunodeficient mice. To complement our findings with clinical evidence, we showed that silencing of ADAM23 gene by DNA promoter hypermethylation in a collection of 94 primary breast tumors was significantly associated with lower distant metastases-free and disease-specific survivals and was an independent prognostic factor for poor disease outcome. Our results strongly support a functional role of ADAM23 during metastatic progression by negatively modulating A v B 3 integrin activation. [Cancer Res 2009;69(13):5546-52]

ADAM23 in Cardiomyocyte Inhibits Cardiac Hypertrophy by Targeting FAK‐AKT Signaling

“…Importantly, ADAM23 could directly interact with αvβ3 integrin through its disintegrin domain. By this way, ADAM23 negatively modulates αvβ3 integrin activation and its expression 18. Based on these findings, we postulate that ADAM23 inhibiting FAK/AKT signaling through constraining integrin to regulate cardiac hypertrophy.…”

“…Compared with other family members, the biological role of ADAM23 largely depends on its disintegrin domain, while its metalloprotease domain remains inactive 7. ADAM23 acts principally as a mediator of intercellular association by binding to integrin and/or other cell‐surface molecules,18, 19 which could participate in the pathologic process of cardiac hypertrophy. However, the exact role of ADAM23 and its possible mechanisms for regulating hypertrophic cardiomyopathy remains unclear.…”

Epigenomics in cancer management

“…52,53 For example, our group has already shown that the adhesion molecule ADAM23 is highly methylated in breast tumors, and this feature is correlated to metastases and a poor prognosis in breast tumors. 54,55 A classic example of a DNA repair gene downregulated by DNA methylation is the MGMT gene, which is silenced by epigenetic mechanisms in brain tumors. 56 Tumors that do not express the gene MGMT are more sensitive to radiotherapy and chemotherapy with temozolomide, and this molecular feature has been used in clinical decisions and disease management for glioblastomas.…”

Pharmaco-epigenomics: discovering therapeutic approaches and biomarkers for cancer therapy

“…A potential biomarker for anti-integrin therapy might be the ADAM23 gene, which acts as a negative regulator of the integrina V b III receptor. ADAM23 is frequently silenced by promoter hypermethylation and as its silencing correlates with tumor progression, it might be associated with the acquisition of an angiogenic and metastatic phenotype (Verbisck et al, 2009). Tumors with ADAM23 hypermethylation might, therefore, depend more on a V integrin signaling for their vessel growth, which would render them more eligible for antiintegrin therapy.…”