γ-Tocotrienol inhibition of galectin-3 expression, distribution and oligomerization in highly metastatic breast cancer cells

Experimental studies were conducted to compare the relative effects of γ-tocotrienol, a natural isoform within the vitamin E family of compounds, with established galectin-3 inhibitor β-lactose, on galectin-3 levels and distribution in highly metastatic human MDA-MB-231, and mouse + SA and TS/A breast cancer cell lines. In contrast to β-lactose, γ-tocotrienol displays a dual-mode binding profile with the carbohydrate recognition domain and hydrophobic pocket located on galectin-3, as determined using Schrödinger molecular modeling. However, treatment with either γ-tocotrienol or β-lactose induces a significant decrease in galectin-3 expression, oligomerization, and a corresponding decrease in fibronectin fibril and lamellipodial protrusion formation, an indication of treatment-induced reversal in epithelial-mesenchymal transition (EMT). These same treatments also caused a significant decrease in galectin-3 Fluorescence Resonance Energy Transfer (FRET) signaling, as compared to the control group, demonstrating the intricate role of galectin-3 in modulating EMT in metastatic breast cancer cells. Combined treatment of doxorubicin with either γ-tocotrienol or β-lactose results in a large increase in doxorubicin levels in the nuclei of metastatic breast cancer cells, the primary site of action for this chemotherapeutic agent. Taken together these findings demonstrate that γ-tocotrienol-induced reversal of EMT in metastatic breast cancer cells is mediated, at least in part, by a disruption in the galectin-3 expression, distribution and function.