Lysophosphatidic acid (LPA) signaling via LPA receptors (LPA(1) to LPA(6)) contributes to the promotion of malignant potency in cancer cells. The cell motile activity are stimulated through the induction of LPA(5) in melanoma cells treated with anticancer drugs. The present study aimed to investigate whether LPA signaling via LPA(5) regulates chemoresistance in melanoma A375 cells. Cells were treated with cisplatin (CDDP) or dacarbazine (DTIC) every 24 h for 2 days. CDDP and DTIC treatment increased LPAR5 expressions. The cell survival rates of A375 cells treated with CDDP and DTIC were significantly decreased by LPA. In addition, LPAR5 expression was markedly elevated in long-term CDDP treated (A375-CDDP) cells. LPA decreased the cell survival rate of A375-CDDP cells treated with CDDP. To evaluate the roles of LPA(5)( )in chemoresistance during tumor progression, highly migratory (A375-R11) cells were established from A375 cells. LPAR(5) expression level was significantly lower in A375-R11 cells than in A375 cells. The cell survival rates of A375-R11 cells treated with CDDP and DTIC were increased, compared with A375 cells. Moreover, we generated LPA(5) knockdown cells from A375 cells. The cell survival rates of A375 cells treated with CDDP and DTIC were significantly elevated by LPA(5) knockdown. These results suggest that LPA signaling via LPA(5) is involved in the modulation of chemoresistance in melanoma A375 cells. (C) 2019 Elsevier Inc. All rights reserved.