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.
Laboratoire d'Oncologie Moléculaire, Centre de recherche BIOMED, Département de Chimie, Université du Québec à Montréal, Quebec, Canada.
Jonathan
J
Pratt
Laboratoire d'Oncologie Moléculaire, Centre de recherche BIOMED, Département de Chimie, Université du Québec à Montréal, Quebec, Canada. Electronic address: annabi.borhane@uqam.ca.
Borhane
B
Annabi
D001343:Autophagy / Q000187:drug effects*; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D003208:Concanavalin A / Q000494:pharmacology*; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053511:Matrix Metalloproteinase 14 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D014617:Vacuoles / Q000187:drug effects
C090121:BNIP3 protein, human; D015415:Biomarkers; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D003208:Concanavalin A; D053614:Janus Kinase 2; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
Autophagy; BNIP3; Concanavalin-A; Glioblastoma; JAK/STAT; MT1-MMP