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

Abstract

Hydrogen peroxide (H₂O₂) is one of reactive oxygen species (ROS) and promotes malignant properties of cancer cells. Lysophosphatidic acid (LPA) signaling via LPA receptor (LPA₁ to LPA₆) 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 H₂O₂ in colon cancer DLD-1 cells. To obtain H₂O₂ treated (DLD- H₂O₂) cells, cells were maintained in culture medium containing H₂O₂ (60 μM) for 2 months. LPAR2 and LPAR4 gene expressions were markedly elevated in DLD-H₂O₂ cells. The cell motility of DLD-H₂O₂ cells was significantly lower than that of DLD-1 cells. DLD-H₂O₂ cell motility was suppressed by LPA₂ knockdown and stimulated by LPA₄ knockdown. The cell survival rates to fluorouracil (5-FU), irinotecan (CPT-11) and oxaliplatin (L-OHP) of DLD-H₂O₂ cells were significantly higher than those of DLD-1 cells. The cell survival rate to 5-FU of DLD-H₂O₂ cells was decreased by LPA₂ knockdown. Conversely, LPA₄ knockdown enhanced the cell survival rate to 5-FU of DLD-H₂O₂ cells. In the tumor microenvironment, high levels of H₂O₂ production are observed under hypoxic conditions. The cell survival rate to 5-FU of DLD-H₂O₂ cells cultured at 1% O₂ was significantly higher than that of DLD-1 cells cultured at 1% O₂, 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 H₂O₂.

Keywords: Cancer cells; Cell functions; Hydrogen peroxide; Hypoxia; LPA receptors.