Isoprenaline induces epithelial–mesenchymal transition in gastric cancer cells

The emerging role of stress-related signaling in regulating cancer development and progression has been recognized. However, whether stress serves as a mechanism to promote gastric cancer metastasis is not clear. Here, we show that the β2-AR agonist, isoprenaline, upregulates expression levels of CD44 and CD44v8-10 in gastric cancer cells. CD44, a cancer stem cell-related marker, is expressed at high levels in gastric cancer tissues, which strongly correlates with the occurrence of epithelial–mesenchymal transition (EMT)-associated phenotypes both in vivo and in vitro. Combined with experimental observations in two human gastric cancer cell lines, we found that β2-AR signaling can initiate EMT. It led to an increased expression of mesenchymal markers, such as α-SMA, vimentin, and snail at mRNA and protein levels, and conversely a decrease in epithelial markers, E-cadherin and β-catenin. Isoprenaline stimulation of β2-AR receptors activates the downstream target STAT3, which functions as a positive regulator and mediated the phenotypic switch toward a mesenchymal cell type in gastric cancer cells. Our data provide a mechanistic understanding of the complex signaling cascades involving stress-related hormones and their effects on EMT. In light of our observations, pharmacological interventions targeting β2-AR-STAT3 signaling can potentially be used to ameliorate stress-associated influences on gastric cancer development and progression.