Abl interactor 1 regulates Src-Id1-matrix metalloproteinase 9 axis and is required for invadopodia formation, extracellular matrix degradation and tumor growth of human breast cancer cells

Abstract

Abl interactor 1 (Abi1) is a key regulator of actin polymerization/depolymerization. The involvement of Abi1 in the development of abnormal cytoskeletal functions of cancer cells has recently been reported. It remains unclear, however, how Abi1 exerts its effects in tumor cells and whether it contributes to tumor progression in vivo. We report here a novel function for Abi1 in the regulation of invadopodia formation and Src-inhibitor of differentiation protein 1 (Id1)-matrix metalloproteinase (MMP)-9 pathway in MDA-MB-231 human breast cancer cells. Abi1 is found in the invadopodia of MDA-MB-231 cells. Epigenetic silencing of the Abi1 gene by short hairpin RNA in MDA-MB-231 cells impaired the formation of invadopodia and resulted in downregulation of the Src activation and Id1/MMP-9 expression. The decreased invadopodia formation and MMP-9 expression correlate with a reduction in the ability of these cells to degrade extracellular matrix. Remarkably, the knockdown of Abi1 expression inhibited tumor cell proliferation and migration in vitro and slowed tumor growth in vivo. Taken together, these results indicate that the Abi1 signaling plays a critical role in breast cancer progression and suggest that this pathway may serve as a therapeutic target for the treatment of human breast cancer.

Enterolobium contortisiliquum Trypsin Inhibitor (EcTI), a Plant Proteinase Inhibitor, Decreases in Vitro Cell Adhesion and Invasion by Inhibition of Src Protein-Focal Adhesion Kinase (FAK) Signaling Pathways

“…Therefore, inhibition of extracellular proteinases and more importantly inhibition of invadopodium formation may be an attractive approach for cancer therapy (35)(36)(37)(38)(39). Moreover, considering the complex proteinase network, an inhibitor capable of interfering in invadopodium formation may be useful for the study of tumor progression as well as the study of the involvement of invadopodia in this process.…”

CDK1-mediated Phosphorylation of Abi1 Attenuates Bcr-Abl-induced F-actin Assembly and Tyrosine Phosphorylation of WAVE Complex during Mitosis

“…Biochemical and Cell Biology Assays-Immunoprecipitation and Western blotting analyses were performed as described previously (31). In brief, cells were lysed in lysis buffer (20 mM Hepes, pH 7.2, 150 mM NaCl, 1% Triton X-100, and 10% glycerol) containing a protease inhibitor mixture and phosphatase inhibitors and incubated with appropriate antibodies bound to Sepharose beads.…”

Crk and Abi1: Binary Molecular Switches That Regulate Abl Tyrosine Kinase and Signaling to the Cytoskeleton

“…breast cancer in vivo and in vitro through activation of Src 80,82 and NWASP. 83,84 Higher levels of Abi1 might lead to PI3 kinase upregulation through SH2 domain interaction as suggested 54,76 and subsequent metabolic changes as a consequence of enhanced PIP3 and Akt signaling as described, for example, for invasive breast cancer.…”