Increase in Sialylated EGFR Levels by Arsenite Enhances EGF‐Dependent EGFR Phosphorylation

ABSTRACT

Although the carcinogenicity of arsenic compounds is well established, the underlying mechanisms remain poorly understood. Cancer cells are known to evade natural killer (NK) cell–mediated cytotoxicity by presenting sialic acids at the termini of cell‐surface glycans, and aberrant sialylation of specific proteins has been implicated in cancer progression. In this study, building on our previous finding that arsenite (As(III)) exposure increases cell‐surface sialic acid levels, we investigated whether As(III) exposure alters the levels of sialylated epidermal growth factor receptor (EGFR) and whether these changes affect downstream signal transduction. We first confirmed that EGFR expressed in A431 cells is modified with α 2–6–linked sialic acid. When A431 cells were exposed to As(III), sialylated EGFR levels increased markedly. Treatment of A431 cells with sialidase significantly suppressed EGF‐dependent EGFR phosphorylation, indicating that sialylated EGFR positively regulates EGF‐induced EGFR phosphorylation in A431 cells. Exposure to As(III) markedly enhanced EGF‐dependent phosphorylation of EGFR and showed a tendency to increase phosphorylation of the downstream signaling molecule ERK; however, sialidase treatment completely abolished this enhancement. Taken together, these results demonstrate that As(III) activates the EGF‐induced phosphorylation cascade by promoting EGFR sialylation.