Lysophosphatidic acid signaling via LPA1 and LPA3 regulates cellular functions during tumor progression in pancreatic cancer cells

Abstract

Lysophosphatidic acid (LPA) signaling via G protein-coupled LPA receptors exhibits a variety of biological effects, such as cell proliferation, motility and differentiation. The aim of this study was to evaluate the roles of LPA₁ and LPA₃ in cellular functions during tumor progression in pancreatic cancer cells. LPA₁ and LPA₃ knockdown cells were generated from PANC-1 cells. The cell motile and invasive activities of PANC-1 cells were inhibited by LPA₁ and LPA₃ knockdown. In gelatin zymography, LPA₁ and LPA₃ knockdown cells indicated the low activation of matrix metalloproteinase-2 (MMP-2) in the presence of LPA. Next, to assess whether LPA₁ and LPA₃ regulate cellular functions induced by anticancer drug, PANC-1 cells were treated with cisplatin (CDDP) for approximately 6 months. The cell motile and invasive activities of long-term CDDP treated cells were markedly higher than those of PANC-1 cells, correlating with the expression levels of LPAR1 and LPAR3 genes. In soft agar assay, the long-term CDDP treated cells formed markedly large sized colonies. In addition, the cell motile and invasive activities enhanced by CDDP were significantly suppressed by LPA₁ and LPA₃ knockdown as well as colony formation. These results suggest that LPA signaling via LPA₁ and LPA₃ play an important role in the regulation of cellular functions during tumor progression in PANC-1 cells.

Keywords: Cisplatin; LPA; LPA receptor; Pancreatic cancer cells; Tumor progression.