Abstract
BackgroundThe Abelson tyrosine kinase (c-Abl) inhibitor STI571 (Glivec®) has been shown to effectively inhibit colorectal cancer cell migration and invasion. The c-Abl substrate abelson interactor 1 (Abi1) is a key regulator of actin reorganization and upregulated in colorectal carcinoma. The specific role of Abi1 in relation to extracellular matrix degradation and effects of targeting Abi1 phosphorylation have not yet been examined. Here, we investigated the role of Abi1 in relation to invasive properties in colorectal cancer.Methods and resultsIn 56 primary human colorectal carcinoma samples, we found overexpression of Abi1 in 39% at the invasive edge of the tumour, associated with an infiltrative phenotype and high-grade tumour cell budding (p = 0.001). To explore the role of Abi1 in vitro, we employed the Abi1 expressing and KRAS-mutated CHD1 model and performed matrix degradation assays that showed Abi1 localization at specific sites of matrix degradation. Moreover, quantification of matrix dissolution demonstrated suppression after RNAi knockdown of Abi1 by 95% (p = 0.001). Importantly, treatment with STI571 did abolish Abi1 Y435-phosphorylation, suppressed the matrix dissolution, decreased fibronectin attachment, and suppressed cell invasion through reconstituted extracellular matrix.ConclusionOur data indicate that phosphorylated Abi1 contributes to the invasive properties of colorectal cancer.
Highlights
The Abelson tyrosine kinase (c-Abl) inhibitor STI571 (Glivec®) has been shown to effectively inhibit colorectal cancer cell migration and invasion
We examined the effect of STI571 on Abelson interactor 1 (Abi1) phosphorylation, metalloproteinase secretion, extracellular matrix (ECM) degradation and colorectal cancer cell invasion
Abi1 mRNA expression patterns in gastrointestinal adenocarcinomas Quantitative Abi1 gene expression data for oesophageal (n = 13), gastric (n = 21), small intestinal (n = 6) and colorectal (n = 505) adenocarcinomas obtained from the GeneSapiens transcriptomics database showed comparable expression levels between tumour entities (Figure 1A)
Summary
The Abelson tyrosine kinase (c-Abl) inhibitor STI571 (Glivec®) has been shown to effectively inhibit colorectal cancer cell migration and invasion. The c-Abl substrate abelson interactor 1 (Abi1) is a key regulator of actin reorganization and upregulated in colorectal carcinoma. Tumour cells facilitate extracellular matrix (ECM) degradation and invasion through the formation of specialized cytoplasmic protrusions, so-called invadopodia [4]. These consist of parallel actin bundles on the basis of a branched actin meshwork and are enriched in proteins that are involved in actin remodelling, including Cortactin, formins of the Diaphanous family and class I nucleation-promoting factors (NPFs) such as WASP or N-WASP [5]. Besides providing the structural basis for invadopodia, branched actin filaments give rise to broad-based lamellipodia that are a prerequisite for cellular migration [5,6]
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