Embelin suppresses pancreatic cancer growth by modulating tumor immune microenvironment.

Since pancreatic carcinoma is largely refractory to conventional therapies, development of novel agents is required for the effective treatment of pancreatic cancer. The objective of this paper was to examine the molecular mechanisms by which embelin inhibited human pancreatic cancer growth in mice by modulating tumor immune microenvironment. Embelin inhibited PANC-1 tumor growth, angiogenesis, and metastasis which were associated with suppression of Akt and Sonic Hedgehog (Shh) pathways. Embelin inhibited the expression of Bcl-2, cyclin D1, CDK2 and CDK6, IL-6 and IL-8, and induced the expression of Bax in tumor tissues. Embelin also reversed epithelial-mesenchymal transition by up-regulating E-cadherin and inhibiting the expression of Snail, Slug and Zeb1. Embelin inhibited pancreatic cancer growth in Kras(G12D) mice by modulating tumor immune microenvironment where CTL, NKT, γδT, NK, and IFNγ (Th1 type) cells were up-regulated, and Th17, PMN-MDSC, IL-6 and IL-8 (Th2 type) immune cells were inhibited. These data suggest that embelin can inhibit pancreatic cancer growth by modulating tumor immune microenvironment and Akt and Shh pathways, and inhibiting inflammation. Embelin may offer therapeutic benefits for the treatment and/or prevention of pancreatic cancer.