Abstract
CD44 is a receptor for hyaluronan (HA) that promotes epithelial-to-mesenchymal transition (EMT), induces cancer stem cell (CSC) expansion, and favors metastasis. Thus, CD44 is a target for the development of antineoplastic agents. In order to repurpose drugs as CD44 antagonists, we performed consensus-docking studies using the HA-binding domain of CD44 and 11,421 molecules. Drugs that performed best in docking were examined in molecular dynamics simulations, identifying etoposide as a potential CD44 antagonist. Ligand competition and cell adhesion assays in MDA-MB-231 cells demonstrated that etoposide decreased cell binding to HA as effectively as a blocking antibody. Etoposide-treated MDA-MB-231 cells developed an epithelial morphology; increased their expression of E-cadherin; and reduced their levels of EMT-associated genes and cell migration. By gene expression analysis, etoposide reverted an EMT signature similarly to CD44 knockdown, whereas other topoisomerase II (TOP2) inhibitors did not. Moreover, etoposide decreased the proportion of CD44+/CD24− cells, lowered chemoresistance, and blocked mammosphere formation. Our data indicate that etoposide blocks CD44 activation, impairing key cellular functions that drive malignancy, thus rendering it a candidate for further translational studies and a potential lead compound in the development of new CD44 antagonists.
Highlights
Breast cancer is the most common noncutaneous cancer in women and the leading cause of cancer‐related mortality in females worldwide
By root‐mean‐square deviation (RMSD) analysis of the starting structure, we examined the stability of the 5 ligand‐protein complexes (Figure 2A)
Etoposide significantly decreased the adhesion of MDA‐MB‐231 cells to a layer of HA dose‐dependently from 50 μM to 47.8 ± 13.2% of control at 200 μM (Figure 3C). These results indicate that etoposide inhibits HA binding to CD44 and CD44‐activated cell functions, supporting its function as a CD44 antagonist
Summary
Breast cancer is the most common noncutaneous cancer in women and the leading cause of cancer‐related mortality in females worldwide. In 2012, over 1.6 million new cases and 520,000 breast cancer‐caused deaths were reported [1]. Despite advances in its treatment, 20% to 30% of patients with early breast cancer will experience relapse with distant metastatic disease [2], necessitating new therapeutic strategies. CD44 is a multidomain transmembrane glycoprotein receptor, the major physiological ligand of which is the glycosamine glycan hyaluronan (HA) [3]. The expression of CD44 and HA correlates with unfavorable clinical outcomes [4,5,6,7], highlighting their function in disease progression. Several isoforms of CD44 are produced by alternative splicing, all of them share the HA binding site [3]
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