Induction of lysophosphatidic acid (LPA) receptor-mediated signaling regulates cell motility and survival to anticancer drugs in cancer cells treated with hydrogen peroxide.

Hydrogen peroxide (HO) is one of reactive oxygen species (ROS) and promotes malignant properties of cancer cells. Lysophosphatidic acid (LPA) signaling via LPA receptor (LPA to LPA) regulates a variety of cellular functions, such as cell growth, migration and differentiation. This study aimed to evaluate the effects of LPA receptors on the cell motility and survival to anticancer drugs by HO in colon cancer DLD-1 cells. To obtain HO treated (DLD- HO) cells, cells were maintained in culture medium containing HO (60 μM) for 2 months. LPAR2 and LPAR4 gene expressions were markedly elevated in DLD-HO cells. The cell motility of DLD-HO cells was significantly lower than that of DLD-1 cells. DLD-HO cell motility was suppressed by LPA knockdown and stimulated by LPA knockdown. The cell survival rates to fluorouracil (5-FU), irinotecan (CPT-11) and oxaliplatin (L-OHP) of DLD-HO cells were significantly higher than those of DLD-1 cells. The cell survival rate to 5-FU of DLD-HO cells was decreased by LPA knockdown. Conversely, LPA knockdown enhanced the cell survival rate to 5-FU of DLD-HO cells. In the tumor microenvironment, high levels of HO production are observed under hypoxic conditions. The cell survival rate to 5-FU of DLD-HO cells cultured at 1% O was significantly higher than that of DLD-1 cells cultured at 1% O, correlating with LPAR2 gene expression. The present results suggest that the induction of LPA receptor-mediated signaling plays an important role in regulating cellular functions of DLD-1 cells treated with HO.