Lysophosphatidic acid receptor-2 (LPA2) and LPA5 regulate cellular functions during tumor progression in fibrosarcoma HT1080 cells

Highlights: • LPAR2 and LPAR5 expressions were elevated by long-term anticancer drug treatment in HT1080 cells. • Highly invasion HT1080-M6 cells were generated from HT1080 cells using Matrigel-coated filters. • HT1080-M6 cell invasion was shown to be 4.5 times higher than that of HT1080 cells. • The cell motile and invasive activities of HT1080-M6 cells were reduced by LPA₂ inhibition. • LPA signaling via LPA₂ is a potent target for the regulation of tumor progression in HT1080 cells. Lysophosphatidic acid (LPA) receptors (LPA₁ to LPA₆) regulate a variety of malignant properties in cancer cells. In the present study, we investigated the roles of LPA receptors in the promotion of cellular functions during tumor progression in fibrosarcoma cells. To obtain long-term anticancer drug treated cells, human fibrosarcoma HT1080 cells were treated with methotrexate (MTX) and cisplatin (CDDP) for 6 months. LPAR2 and LPAR5 expressions were significantly higher in MTX-treated (HT-MTX) cells than in HT1080 cells. The cell motile and invasive activities of HT-MTX cells were significantly elevated compared with HT1080 cells. Although LPAR5 expression was increased in MTX and CDDP treated (HT-M-C) cells, no change of LPAR2 expression was observed. The cell motile and invasive activities of HT-M-C cells were lower than those of HT1080 cells. Moreover, to evaluate whether LPA receptors promote cell invasive activity, highly invasion (HT1080-M6) cells were established from HT1080 cells. The cell invasive activity of HT1080-M6 cells was approximately 4.5 times higher than HT1080 cell invasion. LPAR2 expression was markedly elevated in HT1080-M6 cells compared with HT1080 cells. The high cell invasion activity of HT1080-M6 cells was significantly suppressed by an antagonist of LPA₂, H2L5186303. These results suggest that LPA₂ acts as a key regulator of malignant properties in HT1080 cells.