Figure 7.

LD-mediated lipid mediator production promotes cancer-cell proliferation and tumour growth. (A) Proliferation of MDA-MB-231 cells treated with T863 (DGAT1i) and PF-06427878 (DGAT2i), or an equimolar mix of both DGAT inhibitors (DGATi), grown under nutrient-rich conditions in the absence and presence of hGX sPLA₂. (B, C) Proliferation of MDA-MB-231 cells overexpressing ATGL (ATGL^OE), treated with indomethacin (B) or nordihydroguaiaretic acid (NDGA) (C), in the absence or presence of hGX sPLA₂. (D, E) Tumour growth (D) and corresponding Kaplan–Meier survival curves (E) of mice bearing MDA-MB-231 xenografts and treated daily with the DGAT1 inhibitor T863 or with 0.2% DMSO vehicle. Significance was determined by log-rank (Mantel–Cox) test. (F) DGAT1-inhibitor-induced changes in the abundance of lipid mediators and PUFAs in tumour samples isolated from mice bearing MDA-MB-231 xenografts and treated daily with DGAT1 inhibitor T863 or with 0.2% DMSO vehicle. The volcano plot depicts significant changes (–log₁₀(P value) > 1.30) in individual lipids detected by UPLC-MS/MS in DGAT1i-treated versus vehicle-treated mice and was prepared using log₂-transformed fold-change values and multiple t-test analysis (n = 4 independent experiments). (G) Proliferation of A549 cells overexpressing cPLA₂α (cPLA₂α^OE) and grown in the absence and presence of DGATi, indomethacin and recombinant hGX sPLA₂. (H) Proliferation of MDA-MB-231 cells overexpressing cPLA₂α (cPLA₂α^OE) and grown in the absence and presence of DGATi and recombinant hGX sPLA₂. Data are means ± SEM of three independent experiments. ∗, P < 0.05; ∗∗, P < 0.01; ∗∗∗, P < 0.001 (two-way ANOVA with Tukey (A), Bonferroni (B, C) or Sidak (G, H) adjustments).