title: RIP3 antagonizes a TSC2-mediated pro-survival pathway in glioblastoma cell death.
abstract: Glioblastomas are the deadliest type of brain cancer and are frequently associated with poor prognosis and a high degree of recurrence despite removal by surgical resection and treatment by chemo- and radio-therapy. Photodynamic therapy (PDT) is a treatment well known to induce mainly necrotic and apoptotic cell death in solid tumors. 5-Aminolevulinic acid (5-ALA)-based PDT was recently shown to sensitize human glioblastoma cells (LN-18) to a RIP3 (Receptor Interacting Protein 3)-dependent cell death which is counter-acted by activation of autophagy. These promising results led us to investigate the pathways involved in cell death and survival mechanisms occurring in glioblastoma following PDT. In the present study, we describe a new TSC2 (Tuberous Sclerosis 2)-dependent survival pathway implicating MK2 (MAPKAPK2) kinase and 14-3-3 proteins which conducts to the activation of a pro-survival autophagy. Moreover, we characterized a new RIP3/TSC2 complex where RIP3 is suggested to promote cell death by targeting TSC2-dependent survival pathway. These results highlight (i) a new role of TSC2 to protect glioblastoma against PDT-induced cell death and (ii) TSC2 and 14-3-3 as new RIP3 partners.
authors.affiliation: Laboratory of Virology and Immunology, GIGA-I(3), University of Liège, Liège, Belgium.
authors.forename: Gregory
authors.initials: G
authors.lastname: Fettweis
authors.affiliation: GIGA-Viral Vector Platform, University of Liège, Liège, Belgium.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Di Valentin
authors.affiliation: Laboratory of Virology and Immunology, GIGA-I(3), University of Liège, Liège, Belgium.
authors.forename: Laurent
authors.initials: L
authors.lastname: L'homme
authors.affiliation: Laboratory of Virology and Immunology, GIGA-I(3), University of Liège, Liège, Belgium.
authors.forename: Cédric
authors.initials: C
authors.lastname: Lassence
authors.affiliation: Laboratory of Protein Signaling and Interactions, GIGA-Molecular Biology of Diseases, University of Liège, Liège, Belgium.
authors.forename: Franck
authors.initials: F
authors.lastname: Dequiedt
authors.affiliation: Laboratory for the Analysis of Medicines (LAM), Department of Pharmaceutical Sciences, CIRM, University of Liège, Liège, Belgium.
authors.forename: Marianne
authors.initials: M
authors.lastname: Fillet
authors.affiliation: Laboratory of Virology and Immunology, GIGA-I(3), University of Liège, Liège, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coupienne
authors.affiliation: Laboratory of Virology and Immunology, GIGA-I(3), University of Liège, Liège, Belgium. Electronic address: jpiette@ulg.ac.be.
authors.forename: Jacques
authors.initials: J
authors.lastname: Piette
mesh_terms: D048948:14-3-3 Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000622:Aminolevulinic Acid / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D000071193:Autophagy-Related Protein 7 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D064112:Clustered Regularly Interspaced Short Palindromic Repeats; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008027:Light; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D048948:14-3-3 Proteins; D000622:Aminolevulinic Acid; D000071193:Autophagy-Related Protein 7; D047908:Intracellular Signaling Peptides and Proteins; D017319:Photosensitizing Agents; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000099190:MAP-Kinase-Activated Kinase 2; C000624653:TSC2 protein, human; C000624655:Tsc2 protein, rat; C572235:YWHAZ protein, human; C119705:RIPK3 protein, human; C509349:ATG7 protein, human
keywords: Autophagy regulation; Glioblastoma; MAP kinases; Photodynamic therapy; Programmed necrosis