title: NF-kappaB inhibition improves the sensitivity of human glioblastoma cells to 5-aminolevulinic acid-based photodynamic therapy.
abstract: Glioblastoma constitute the most frequent and deadliest brain tumors of astrocytic origin. They are very resistant to all current therapies and are associated with a huge rate of recurrence. In most cases, this type of tumor is characterized by a constitutive activation of the nuclear factor-kappaB (NF-κB). This factor is known to be a key regulator of various physiological processes such as inflammation, immune response, cell growth or apoptosis. In the present study, we explored the role of NF-κB activation in the sensitivity of human glioblastoma cells to a treatment by 5-aminolevulinic acid (5-ALA)-based photodynamic therapy (PDT). 5-ALA is a physiological compound widely used in PDT as well as in tumor photodetection (PDD). Our results show that inhibition of NF-κB improves glioblastoma cell death in response to 5-ALA-PDT. We then studied the molecular mechanisms underlying the cell death induced by PDT combined or not with NF-κB inhibition. We found that apoptosis was induced by PDT but in an incomplete manner and that, unexpectedly, NF-κB inhibition reduced its level. Oppositely PDT mainly induces necrosis in glioblastoma cells and NF-κB is found to have anti-necrotic functions in this context. The autophagic flux was also enhanced as a result of 5-ALA-PDT and we demonstrate that stimulation of autophagy acts as a pro-survival mechanism confering protection against PDT-mediated necrosis. These data point out that 5-ALA-PDT has an interesting potential as a mean to treat glioblastoma and that inhibition of NF-κB renders glioblastoma cells more sensitive to the treatment.
authors.affiliation: Virology and Immunology Unit, GIGA-R, GIGA B34, University of Liège, Liège Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coupienne
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bontems
authors.forename: Michael
authors.initials: M
authors.lastname: Dewaele
authors.forename: Noemi
authors.initials: N
authors.lastname: Rubio
authors.forename: Yvette
authors.initials: Y
authors.lastname: Habraken
authors.forename: Simone
authors.initials: S
authors.lastname: Fulda
authors.forename: Patrizia
authors.initials: P
authors.lastname: Agostinis
authors.forename: Jacques
authors.initials: J
authors.lastname: Piette
mesh_terms: D000622:Aminolevulinic Acid / Q000494:pharmacology*; D017209:Apoptosis; D001343:Autophagy; D001932:Brain Neoplasms; D005909:Glioblastoma; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009336:Necrosis; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: D016328:NF-kappa B; D017319:Photosensitizing Agents; D000622:Aminolevulinic Acid