Abstract
Anoikis-resistance is a critical step in cancer progression, especially during the process of metastasis. During this phase, the cancer phenotype that causes cell survival in detachment conditions, drug resistance, and epithelial-to-mesenchymal transition (EMT) is altered. Inhibition of anoikis-resistance can potentially be the molecular target in cancer therapy. Alpha-mangostin, an active compound in Garcinia mangostana, has been reported for its cell-death induction and its chemosensitizing and anti-metastatic properties in many cancer cell types, such as ovarian cancer, lung cancer, and hepatocellular carcinoma. We, therefore, have investigated whether alpha-mangostin could sensitize anoikis in human hepatocellular carcinoma (HepG2). The established anoikis-resistant HepG2 displayed more aggressive malignant behaviors, including rapid proliferation, doxorubicin resistance, up-regulated anti-apoptotic protein levels, and EMT phenotype. Alpha-mangostin significantly sensitized anoikis in HepG2 through the inhibition of cell survival by induced caspase-9, caspase-8 and caspase-3 activities, increased pro-apoptotic protein (Bax, Bim, t-Bid) levels, and decreased anti-apoptotic protein (c-FLIP, Mcl-1) levels. Besides, alpha-mangostin significantly reduced cell re-adhesion and migration, matrix metalloproteinases-2 (MMP-2) and MMP-9 secretions, and EMT-involved protein (N-cadherin, αV, β1 integrin, and vimentin) expressions. AKT and ERK signaling pathways were dramatically suppressed, which indicated that alpha-mangostin inhibited anoikis-resistance via the inhibition of these pathways in HepG2. These findings support the development of alpha-mangostin to be used in the treatment of anoikis-resistant liver cancer.