We explored the anti-cancer capacity of (−)-oleocanthal in human hepatocellular carcinoma (HCC). (−)-Oleocanthal inhibited proliferation and cell cycle progression and induced apoptosis in HCC cells in vitroand suppressed tumor growth in an orthotopic HCC model. (−)-Oleocanthal also inhibited HCC cell migration and invasion in vitro and impeded HCC metastasis in an in vivo lung metastasis model. ( )-Oleocanthal acted by inhibiting epithelial-mesenchymal transition (EMT) through downregulation Twist, which is a direct target of STAT3. (−)-Oleocanthal also reduced STAT3 nuclear translocation and DNA binding activity, ultimately downregulating its downstream effectors, including the cell cycle protein Cyclin D1, the anti-apoptotic proteins Bcl-2 and survivin, and the invasion-related protein MMP 2. Overexpression of constitutively active STAT3 partly reversed the anti cancer effects of (−)-oleocanthal, which inhibited STAT3 activation by decreasing the activities of JAK1 and JAK2 and increasing the activity of SHP-1. These data suggest that (−)-oleocanthal may be a promising candidate for HCC treatment.
(−)-Oleocanthal inhibits HCC migration and invasion in vitro and in vivo
To explore the effect of (−)-oleocanthal on cell motility, Huh-7 and HepG2 cells were treated with 10 or 15 μM (−)-oleocanthal; these doses did not affect cell viability. (−)-Oleocanthal decreased Huh-7 and HepG2 cell migration ability in a wound-healing assay (Figure (Figure4A).4A). (−)-Oleocanthal also suppressed Huh-7 and HepG2 cell invasion ability in a matrigel-coated transwell assay (Figure (Figure4B).4B). To further investigate the effects of (−)-oleocanthal on HCC in vivo, we injected luciferase-expressing HCCLM3 cells into the tail veins of nude mice and monitored tumor metastasis using bioluminescence imaging. Illumination signals were stronger in control group than in the (−)-oleocanthal-treated group (Figure (Figure4C4C and and4E).4E). At the end of treatment, the mice were sacrificed and lungs were excised to perform hematoxylin and eosin staining. The (−)-oleocanthal-treated group had fewer and smaller lung metastases compared to the control group (Figure (Figure4D4D and and4F4F).
Authors: Tiemin Pei,#1 Qinghui Meng,#1 Jihua Han,#1 Haobo Sun,1 Long Li,1 Ruipeng Song,1 Boshi Sun,1 Shangha Pan,1Desen Liang,1 and Lianxin Liu