Lysophosphatidic acid receptor-2 (LPA2)-mediated signaling enhances chemoresistance in melanoma cells treated with anticancer drugs

Lysophosphatidic acid (LPA) signaling through LPA receptors (LPA 1 to LPA 6 ) regulates a variety of malignant properties in cancer cells. Recently, we show that LPA 2 expression is elevated by long-term cisplatin (CDDP) treatment in melanoma A375 cells. In the present study, we investigated whether LPA 2 -mediated signaling is involved in the modulation of chemoresistance in A375 cells. In cell survival assay, cells were treated with CDDP and dacarbazine (DTIC) every 24 h for 2 days. The cell survival rates to CDDP and DTIC were markedly increased by an LPA 2 agonist, GRI-977143. To validate the effects of LPA 2 on cell survival, LPA 2 knockdown cells were generated from A375 cells. The cell survival rates elevated by GRI-977143 were suppressed by LPA 2 knockdown. To evaluate the roles of LPA 2 -mediated signaling in cell survival, cells were pretreated with a Gi protein inhibitor, pertussis toxin (PTX). In the presence of GRI-977143, the cell survival rates to CDDP and DTIC were significantly lower in PTX-treated cells than in untreated cells. In addition, pretreatment of an adenylyl cyclase inhibitor, SQ22536, increased the cell survival of A375 cells treated with CDDP and DTIC. These results suggest that LPA 2 -mediated signaling plays an important role in the enhancement of chemoresistance of A375 cells treated with anticancer drugs.