Role for CCN1 in lysophosphatidic acid response in PC‐3 human prostate cancer cells

Abstract

Lysophosphatidic acid (LPA) and sphingosine 1‐phosphate (S1P) are bioactive phospholipids that act as mitogens in various cancers. Both LPA and S1P activate G‐protein coupled receptors (GPCRs). We examined the role of CCN1/CYR61, an inducible matricellular protein, in LPA‐induced signal transduction in PC‐3 human prostate cancer cells. We found that both LPA and S1P induced expression of CCN1 and CCN2 within 2–4 h. CCN1 was induced by 18:1‐LPA, but not by 18:0‐, 18:2‐, or 18:3‐LPAs. A free fatty acid receptor‐4 agonist inhibited LPA‐induced CCN1 induction. CCN1 appeared in the ECM within 2 h after LPA addition. LPA caused biphasic activation of Erk MAPK, with an initial peak at 10–20 min followed by a later phase after 6 h. LPA increased adhesion of PC‐3 cells to culture substrates (standard culture plates, fibronectin, or extracellular matrix) at 2 h, an intermediate event between early and late LPA signals. Knockdown of CCN1 suppressed LPA‐induced adhesion to ECM or fibronectin. ECM from CCN1 knockdown cells was a poor substrate for adhesion, as compared to ECM from control cells. These results suggest that CCN1 contributes to LPA responses in the tumor microenvironment. The LPA‐CCN1 axis holds promise for the development of novel therapeutic strategies in cancer.