BPB Reports

Lysophosphatidic acid (LPA) is a lysophospholipid produced via autotoxin enzymatic activity that acts as a lipid mediator and induces several physiological effects.1–3) Several reports demonstrated that LPA activates mitogen-activated protein kinases (MAPKs), phosphoinositide 3-kinase, and low-molecular-weight G-proteins by binding to at least seven specific G-protein coupled receptors known as LPA receptors.1–7) LPA receptors can be classified into two major subfamilies. Specifically, LPA1, LPA2, and LPA3, which share > 50% homology, are known as endothelial differentiation gene members, whereas LPA4, LPA5, LPA6, and a putative LPA receptor, GPR87 are members of the P2Y purinergic family.5–7) These LPA receptors are expressed in various mammalian cells to transduce LPA-induced biological signals.2) However, unwanted ectopic activation was known to contribute to the regulation of cell viability, proliferation, migration, and invasion in several human tumors.6) Similarly to these reports, our previous study also demonstrated that the colony dispersal of human squamous carcinoma-derived A431 cells was induced by LPA through LPA1 and GPR87 activation.8) In addition, we revealed that epidermal growth factor (EGF) receptor transactivation and p38 MAPK, Akt, and JNK signaling activation are strongly associated with this cell dispersal.8) Furthermore, we also found that LPA stimulation of A431 cells causes a change in subcellular localization of E-cadherin from the plasma membrane to the cytoplasm. This colony dispersal and changes in the subcellular localization of E-cadherin comprise epithelial-mesenchymal transition (EMT), which occurs during tumor migration and transition.9,10) In addition to A431 cells, the malignant transformation of tumors by LPA has been proven in other cell types. Our recent study demonstrated that the migration of human cervical carcinoma-derived ME180 cells was also induced by LPA through LPA1 and GPR87 activation.11) However, unlike A431 cells, ME180 cell migration was revealed to involve transactivation of EGF receptors and activation of Erk, p38 MAPK, and JNK but not Akt signaling.11) These reports support the hypothesis that ectopic activation of LPA receptor strongly contributes to the malignant progression of tumor. Endoplasmic reticulum (ER) plays a crucial role in the synthesis of membrane and secretory proteins, lipid biosynthesis, and homeostasis of intracellular Ca2+ levels. Various stresses, including hypoxia, glucose starvation, and viral infection, affect ER function and lead to ER stress, which is characterized by accumulation of unfolded proteins in the ER. As proReport