The 12-LOX/12-HETE/GPR31 metabolic pathway promotes tumor-associated macrophage M2 polarization mediated pancreatic cancer development.

BACKGROUND: The 12-lipoxygenase (12-LOX)/12-hydroxyeicosatetraenoic acid (12-HETE) pathway is associated with various tumors. M2 macrophages in the tumor microenvironment promote tumorigenesis and progression. However, the role of the 12-LOX/12-HETE/G protein-coupled receptor 31 (GPR31) metabolic pathway and its relationship with M2 macrophages remains unclear in pancreatic cancer (PC). METHODS: The expression levels of 12-LOX, GPR31, and 12-HETE were detected in PC and mouse PC models using western blot and enzyme-linked immunosorbent assays (ELISA). In vivo and in vitro experiments were conducted using the 12-LOX inhibitor ML355 to investigate the role of the 12-LOX/12-HETE/GPR31 metabolic pathway in M2 macrophage polarization and tumor progression through flow cytometry, reverse transcription polymerase chain reaction (RT-PCR), 5-Ethynyl-20-deoxyuridine (EdU) assays, and Transwell experiments. RESULTS: The 12-LOX/12-HETE/GPR31 metabolic pathway is expressed actively in PC. Inhibition of 12-LOX in a mouse model of pancreatic cancer suppressed the expression of this metabolic pathway, retarded tumor growth, and reduced the polarization of macrophages towards the M2 type. In vitro, co-culturing PC cell line PANC-1 with macrophages and selectively inhibiting 12-LOX influenced the proliferation, migration, and invasion of PC cells. Inhibiting 12-LOX did not suppress the function of individual PC cells, but it inhibited the development of PC cells co-cultured with macrophages. Moreover, inhibiting 12-LOX reduced the co-cultured M2 macrophages. CONCLUSION: This study, through in vivo and in vitro experiments, reveals that the 12-LOX/12-HETE/GPR31 metabolic pathway affects the growth, migration, and invasion of PC by modulating M2 macrophage polarization patterns.