LPA2 receptor mediates mitogenic signals in human colon cancer cells

Lysophosphatidic acid (LPA) is a mediator of multiple cellular responses. LPA mediates its effects predominantly through the G protein-coupled receptors LPA(1), LPA(2), and LPA(3). In the present work, we studied LPA(2)-mediated signaling using human colon cancer cell lines, which predominantly express LPA(2). LPA(2) activated Akt and Erk1/2 in response to LPA. LPA mediated Akt activation was inhibited by pertussis toxin (PTX), whereas Erk1/2 activation was completely inhibited by a blocker of phospholipase C beta, U-73122. LPA also induced interleukin-8 (IL-8) synthesis in the colon cancer cells by primarily activating LPA(2) receptor. We also found that LPA(2) interacts with Na+/H+ exchanger regulatory factor 2 (NHERF2). Activation of Akt and Erk1/2 was significantly attenuated by silencing of NHERF2 expression by RNA interference, suggesting a pivotal role of NHERF2 in LPA(2)-mediated signaling. We found that expression of LPA(2) was elevated, whereas expression of LPA(1) downregulated in several types of cancers, including ovarian and colon cancer. We conclude that LPA(2) is the major LPA receptor in colon cancer cells and cellular signals by LPA(2) are largely mediated through its ability to interact with NHERF2.