title: Smac Mimetic-Induced Upregulation of CCL2/MCP-1 Triggers Migration and Invasion of Glioblastoma Cells and Influences the Tumor Microenvironment in a Paracrine Manner.
abstract: Second mitochondria-derived activator of caspase (Smac) mimetics are considered as promising anticancer therapeutics that are currently under investigation in early clinical trials. They induce apoptosis by antagonizing inhibitor of apoptosis proteins, which are frequently overexpressed in cancer. We previously reported that Smac mimetics, such as BV6, additionally exert non-apoptotic functions in glioblastoma (GBM) cells by stimulating migration and invasion in a nuclear factor kappa B (NF-κB)-dependent manner. Because NF-κB target genes mediating these effects are largely unknown, we performed whole-genome expression analyses. Here, we identify chemokine (C-C motif) ligand 2 (CCL2) as the top-listed NF-κB-regulated gene being upregulated upon BV6 treatment in GBM cells. BV6-induced upregulation and secretion of CCL2 are required for migration and invasion of GBM cells because knockdown of CCL2 in GBM cells abolishes these effects. Co-culture experiments of GBM cells with non-malignant astroglial cells reveal that BV6-stimulated secretion of CCL2 by GBM cells into the supernatant triggers migration of astroglial cells toward GBM cells because CCL2 knockdown in BV6-treated GBM cells impedes BV6-stimulated migration of astroglial cells. In conclusion, we identify CCL2 as a BV6-induced NF-κB target gene that triggers migration and invasion of GBM cells and exerts paracrine effects on the GBM's microenvironment by stimulating migration of astroglial cells. These findings provide novel insights into the biological functions of Smac mimetics with important implications for the development of Smac mimetics as cancer therapeutics.
authors.affiliation: Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Germany.
authors.forename: Carina
authors.initials: C
authors.lastname: Lindemann
authors.affiliation: Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Germany.
authors.forename: Viola
authors.initials: V
authors.lastname: Marschall
authors.affiliation: Institute of Biochemistry I, Goethe-University, Frankfurt, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Weigert
authors.affiliation: Pediatric Hematology and Oncology, University Children's Hospital, Goethe-University, Frankfurt, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klingebiel
authors.affiliation: Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Germany; German Cancer Consortium (DKTK) Heidelberg, Germany; German Cancer Research Center (DKFZ) Heidelberg, Germany. Electronic address: simone.fulda@kgu.de.
authors.forename: Simone
authors.initials: S
authors.lastname: Fulda
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D032701:Biomimetics; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D018920:Coculture Techniques; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D019899:Paracrine Communication; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; C111835:CCL2 protein, human; D018932:Chemokine CCL2; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D009842:Oligopeptides; D012333:RNA, Messenger