The differential effects of ER stress inducers on LPA-induced A431 cell dispersion

抄録

Lysophosphatidic acid (LPA) is a small ubiquitous lipid found in vertebrate and non-vertebrate organisms that mediates diverse biological actions. LPA activates MAP kinases, PI3-kinase, and low molecular weight G-proteins by binding to multiple LPA receptors (LPA_1-6 receptors and GPR87). We previously demonstrated that colonies of A431 cells, a human epidermoid carcinoma, were dispersed by activation of LPA₁ receptor and GPR87. This LPA-induced A431 cell dispersion is accompanied by epithelial-to-mesenchymal transition (EMT) process, and is thought to be contribute to tumor progression. The endoplasmic reticulum (ER) stress response has been implicated in tumor progression and growth. Recent study showed that the activation of IRE1α-XBP1 pathway promotes tumor progression and EMT in colorectal carcinoma. However, other report showed that preconditioning of ER stress prevents TGF-β1-induced EMT and apoptosis. To investigate the effect of ER stress preconditioning on LPA-induced cell dispersion, we analyze the crosstalk between LPA-induced MAPK signaling and ER stress response using A431 cells. MTT assay showed that low-concentration of tunicamycin (Tm: up to 0.5 ng/mL) and thapsigargin (Tg: up to 1.0 nM), which induced ER stress, exhibited no toxic effects to the cells. Interestingly, preconditioning of Tm-induced ER stress inhibits LPA-induced A431 cell dispersion, whereas Tg-induced ER stress promotes cell dispersion. Furthermore, western blot analysis showed that LPA-induced Akt phosphorylation were prevented by pretreatment of Tm. On the other hand, LPA-induced p38-MAPK phosphorylation were enhanced by pretreatment of Tg. These results indicate that the ER stress inducers differentially effect on LPA-induced A431 cell dispersion via accelerate or decelerate LPA signals.