Lysophosphatidic acid (LPA) receptor signaling modulates cellular functions of colon cancer cells under cobalt chloride-induced hypoxic conditions

Abstract

In the tumor microenvironment (TME), hypoxia is critical in promoting tumor invasiveness and progression. Cobalt chloride (CoCl₂) mimics hypoxia by inducing comparable cellular responses. Lysophosphatidic acid (LPA) receptors (LPA₁ to LPA₆) play key roles in regulating cancer cell functions. In this study, we investigated the impact of LPA receptor signaling on malignant properties of colon cancer DLD-1 cells under hypoxic condition induced by CoCl₂. LPAR1 and LPAR2 expression levels were elevated in DLD-1 cells treated with CoCl₂. CoCl₂ treatment also stimulated DLD-1 cell motility. This enhanced motility induced by CoCl₂ was reduced with LW6 (HIF-1 inhibitor). Additionally, the motility of CoCl₂-treated DLD-1 cells was suppressed by AM966 (LPA₁ antagonist) and enhanced by GRI-977143 (LPA₂ agonist). Conversely, CoCl₂ treatment decreased DLD-1 cell invasion. While AM966 further inhibited cell invasion, GRI-977143 elevated it. The cell viability to fluorouracil (5-FU) was higher in CoCl₂-treated DLD-1 cells. This increased viability to 5-FU was further enhanced by both AM966 and GRI-977143. When CoCl₂-treated DLD-1 cells were cultured in low-glucose media, LPAR1 expression was upregulated compared to high-glucose media, while LPAR2 expression was downregulated. Additionally, motility and invasion in CoCl₂-treated DLD-1 cells were further stimulated under low-glucose conditions. These results suggest that LPA receptor signaling contributes to the malignant potential of DLD-1 cells in a hypoxic environment induced by CoCl₂ treatment.