Induction of autophagy biomarker BNIP3 requires a JAK2/STAT3 and MT1-MMP signaling interplay in Concanavalin-A-activated U87 glioblastoma cells.

Plant lectins have been considered as possible anti-tumor drugs because of their property to induce autophagic cell death. Given that expression of membrane type-1 matrix metalloproteinase (MT1-MMP) has been found to regulate expression of the autophagy biomarker Bcl-2/adenovirus E1B 19kDa interacting protein 3 (BNIP3), we sought to investigate possible signaling interplay mechanisms between MT1-MMP and BNIP3 in Concanavalin-A (ConA) lectin-activated U87 glioblastoma cells. ConA induced acidic vacuole organelle formation as well as BNIP3 and MT1-MMP gene and protein expressions, whereas only BNIP3 expression was dose-dependently inhibited by the JAK2 tyrosine kinase inhibitor AG490 suggesting a requirement for some STAT-mediated signaling. Gene silencing of MT1-MMP and of STAT3 abrogated ConA-induced STAT3 phosphorylation and BNIP3 expression. Correlative analysis shows that STAT3 signaling events occur downstream from MT1-MMP induction. Overexpression of a full length MT1-MMP recombinant protein led to increased BNIP3 gene and protein expressions. The cytoplasmic domain of MT1-MMP was also found necessary for transducing STAT3 phosphorylation. Among JAK1, JAK2, JAK3, and TYK2, only JAK2 gene silencing abrogated ConA's effects on MT1-MMP and BNIP3 gene and protein expressions. Our study elucidates how MT1-MMP signals autophagy, a process which could contribute to the chemoresistance phenotype in brain cancer cells.