Abstract
Regulation of cellular actin dynamics is pivotal in driving cell motility. During cancer development, cells migrate to invade and spread; therefore, dysregulation of actin regulators is often associated with cancer progression. Here we report the role of ABRACL, a human homolog of the Dictyostelium actin regulator Costars, in migration and tumorigenic growth of cancer cells. We found a correlation between ABRACL expression and the migratory ability of cancer cells. Cell staining revealed the colocalization of ABRACL and F-actin signals at the leading edge of migrating cells. Analysis of the relative F-/G-actin contents in cells lacking or overexpressing ABRACL suggested that ABRACL promotes cellular actin distribution to the polymerized fraction. Physical interaction between ABRACL and cofilin was supported by immunofluorescence staining and proximity ligation. Additionally, ABRACL hindered cofilin-simulated pyrene F-actin fluorescence decay in vitro, indicating a functional interplay. Lastly, analysis on a colorectal cancer cohort demonstrated that high ABRACL expression was associated with distant metastasis, and further exploration showed that depletion of ABRACL expression in colon cancer cells resulted in reduced cell proliferation and tumorigenic growth. Together, results suggest that ABRACL modulates actin dynamics through its interaction with cofilin and thereby regulates cancer cell migration and participates in cancer pathogenesis.
Highlights
Given that ABRACL and Dictyostelium Costars share remarkable sequence similarity and that ABRACL can rescue the migration defect of Costars-deficient Dictyostelium cells [6], we set out to test the role of ABRACL in cancer cell migration
We found that MDA-MB-231 breast cancer cells with transient overexpression of HA-ABRACL showed increased migration as compared to that of control cells in the Transwell assay (Figure 1A)
As cell migration is deemed pivotal in cancer pathogenesis, and because our findings suggested that ABRACL may regulate cell motility through modulating actin dynamics, we were prompted to investigate the expression of ABRACL in clinical specimens
Summary
Therapeutic strategies that target cell migration are potentially effective in curbing cancer progression and improving patient outcomes To develop these migration-targeting therapeutics, a thorough understanding of the mechanisms underlying cancer cell movements is crucial. Much remains to be learned about the molecular linkages between the aforementioned steps and the intricate regulation of the entire cell migration process To bridge these knowledge gaps, we have previously performed genetic screening for novel regulators of chemotaxis in the simple eukaryotic model system Dictyostelium discoideum and discovered Costars as a regulator of the actin cytoskeleton and cell motility [6]. Analyses revealed the upregulation of ABRACL expression in clinical specimens of cancerous tissues and an association of ABRACL expression with proliferation and tumorigenic growth of colorectal cancer cells
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