Pseudostellaria heterophylla Extract Polysaccharide H-1-2 Suppresses Pancreatic Cancer by Inhibiting Hypoxia-Induced AG2

We aimed to examine the therapeutic potential of polysaccharide H-1-2, a bioactive component of Pseudostellaria heterophylla, against pancreatic cancer, as well as to demonstrate the underlying molecular mechanisms. Invasion and migration of pancreatic cells treated with H-1-2 were evaluated. A xenograft tumor mouse model was established to assess the effect of H-1-2 on tumor growth. Expression levels of hypoxic inducible factor-1α (HIF1α) and anterior gradient 2 (AGR2) were measured in pancreatic cells after H-1-2 treatment. Luciferase report and chromatin immunoprecipitation assays were conducted to investigate HIF1α regulation on AGR2. AGR2 expression was re-introduced into pancreatic cells to assess the role of AGR2 as a downstream effector of hypoxia after H-1-2 treatment. H-1-2 inhibited invasion and migration of pancreatic cancer cells, repressed xenograft pancreatic tumor growth, and increased survival of mice. H-1-2 repressed AGR2 expression in pancreatic cancer cells through the hypoxia response element (HRE) in its promoter region. Ectopic AGR2 expression partially negated the H-1-2 inhibitory effect on invasion and migration of pancreatic cells and on xenograft pancreatic tumors growth, and it also compromised the H-1-2 promotional effect on survival of mice. We conclude that H-1-2 suppresses pancreatic cancer by inhibiting hypoxia-induced AGR2 expression, supporting further investigation into its efficacy against pancreatic cancer in clinical settings.