RIP3 antagonizes a TSC2-mediated pro-survival pathway in glioblastoma cell death

Biochim Biophys Acta Mol Cell Res. 2017 Jan;1864(1):113-124. doi: 10.1016/j.bbamcr.2016.10.014. Epub 2016 Oct 27.

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.

Keywords: Autophagy regulation; Glioblastoma; MAP kinases; Photodynamic therapy; Programmed necrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / antagonists & inhibitors
  • 14-3-3 Proteins / genetics*
  • 14-3-3 Proteins / metabolism
  • Aminolevulinic Acid / metabolism
  • Aminolevulinic Acid / pharmacology*
  • Animals
  • Autophagy / drug effects
  • Autophagy / genetics
  • Autophagy-Related Protein 7 / antagonists & inhibitors
  • Autophagy-Related Protein 7 / genetics
  • Autophagy-Related Protein 7 / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Gene Expression Regulation, Neoplastic*
  • Gene Silencing
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Light
  • Neuroglia / drug effects*
  • Neuroglia / metabolism
  • Neuroglia / pathology
  • Photochemotherapy
  • Photosensitizing Agents / metabolism
  • Photosensitizing Agents / pharmacology*
  • Protein Binding
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Rats
  • Receptor-Interacting Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / antagonists & inhibitors
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism

Substances

  • 14-3-3 Proteins
  • Intracellular Signaling Peptides and Proteins
  • Photosensitizing Agents
  • RNA, Small Interfering
  • TSC2 protein, human
  • Tsc2 protein, rat
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • YWHAZ protein, human
  • Aminolevulinic Acid
  • MAP-kinase-activated kinase 2
  • Protein Serine-Threonine Kinases
  • RIPK3 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • ATG7 protein, human
  • Autophagy-Related Protein 7