Pomegranate root extract possesses anti-metastatic potential by suppressing invasiveness and vasculogenic mimicry capability of cancer cells

Cancer metastasis is a serious problem in cancer treatment. Metastasis is driven by cancer invasiveness and facilitated by angiogenesis of endothelial cells. Collective evidence revealed that highly invasive cancer cells possess vasculogenic mimicry (VM) capability by forming non-endothelial capillaries that mimic blood vessels. Moreover, VM also resists anti-angiogenic drugs. Thus, anti-invasion and <i>anti</i>-VM are necessary approaches required for anti-metastasis therapy. Pomegranate plants (<i>Punica granatum</i> L.) have been used in traditional medicines since ancient times. Different parts of the pomegranate tree possess the ability to inhibit cancer cell invasion and migration, but there is no report for pomegranate roots. This study aimed to explore anti-metastatic and <i>anti</i>-VM effects of pomegranate root extract (PR) in a human lung cancer cell line (A549) and a VM-forming human hepatocellular carcinoma cell line (SK-Hep-1). At less cytotoxic concentrations (lower than IC₂₀ values), PR dose-dependently reduced invasion, migration, and MMPs production in both A549 and SK-Hep-1 cell lines. PR also inhibited VM formation in SK-Hep-1 cells. Mechanistic studies revealed that, in A549 cells, PR inhibited hepatocyte growth factor (HGF)-induced activation of MET and its downstream AKT and ERK pathways. During VM formation of SK-Hep-1 cells, PR downregulated AKT and ERK signaling pathways without affecting their upstream activator, FAK phosphorylation. Phytochemical profiling of PR analyzed by LC-MS revealed tannins and ellagic acid derivatives were the major classes of natural products present in PR. This research reveals a novel health benefit of pomegranate roots in cancer metastasis therapy.