Diet-derived chemoprevention of epithelial-to-mesenchymal transition through targeting of MT1-MMP-mediated signaling in U87 brain cancer cells

Souad Djediai, Sahily Rodriguez Torres, Borhane Annabi

Laboratoire d'Oncologie Moléculaire, Département de chimie, and CERMO-FC, Université du Québec à Montréal

BACKGROUND: Transforming growth factor (TGF)-β triggers metastasis through epithelial-mesenchymal transition (EMT) to which a role for a membrane type-1 matrix metalloproteinase (MT1-MMP) has been ascribed. Whereas drug design strategies targeting the TGFβ signaling pathway have been envisioned, the effects of the chemopreventive diet-derived catechins against MT1-MMP-mediated signaling remain unexplored. OBJECTIVES: Here, we questioned whether the anti-cancerous properties of the green tea-derived epigallocatechin gallate (EGCG) alter EMT, and whether a crosstalk exists between TGFb- and MT1-MMP-mediated signaling. METHODS: EMT was triggered by TGFb and an inducer of MT1-MMP, Concanavalin A (ConA), in U87 glioblastoma cells in the presence or not of EGCG. Gene and protein expressions of EMT biomarkers Snail and Fibronectin (FN) were assessed by RT-qPCR and Western blotting. Transient gene silencing was performed with transfection of specific siRNA. Differential gene arrays were used to assess the extent of crosstalk between TGFb and ConA. RESULTS: TGFb and ConA triggered Snail and FN expressions in a dose-dependent manner. Those inductions were antagonized by EGCG as well as by the TGFb receptor kinase inhibitor Galunisertib. Silencing of MT1-MMP prevented the induction of Snail by ConA, whereas silencing of Snail was unable to prevent induction of MT1-MMP. Moreover, only ConA induced STAT3 and SRC phosphorylation suggesting these pathways to be involved in the MT1-MMP signaling axis that lead to Snail induction. CONCLUSION: We provide evidence for a new signaling axis linking MT1-MMP to TGFb-mediated EMT induction. We also demonstrate that such process can be prevented through the action of EGCG.