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5-ALA-PDT induces RIP3-dependent necrosis in glioblastoma

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Abstract

Glioblastoma constitute the most frequent and deadliest brain tumors of astrocytic origin. They are resistant to all current therapies and are associated with a high rate of recurrence. Glioblastoma were previously shown to respond to treatments by 5-aminolevulinic acid (5-ALA)-based photodynamic therapy (PDT) mainly by activating a necrotic type of cell death. The receptor-interacting protein 3 (RIP3) has recently been outlined as a key mediator of this caspase-independent form of programmed cell death. In the present study, we analyzed the necrotic mechanism induced by 5-ALA-PDT in human glioblastoma cells and explored the role of RIP3 in this context. Our results show that PDT-induced necrosis is dependent on RIP3, which forms aggregates and colocalizes with RIP1 following photosensitization. We demonstrate that PDT-mediated singlet oxygen production is the cause of RIP3-dependent necrotic pathway activation. We also prove that PDT induces the formation of a pro-necrotic complex containing RIP3 and RIP1 but lacking caspase-8 and FADD, two proteins usually part of the necrosome when TNF-α is used as a stimulus. Thus, we hypothesize that PDT might lead to the formation of a different necrosome whose components, besides RIP1 and RIP3, are still unknown. In most cases, glioblastoma are characterized by a constitutive activation of NF-κB. This factor is a key regulator of various processes, such as inflammation, immune response, cell growth or apoptosis. Its inhibition was shown to further sensitize glioblastoma cells to PDT-induced necrosis, however, no difference in RIP3 upshift or aggregation could be observed when NF-κB was inhibited.

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Authors and Affiliations

  1. Virology and Immunology Unit, GIGA-Research, University of Liège, Belgium

    Isabelle Coupienne, Grégory Fettweis, Noemí Rubio & Jacques Piette

  2. Cell Death Research and Therapy Laboratory, Department of Molecular Cell Biology, Faculty of Medicine, Catholic University of Leuven, Belgium

    Noemí Rubio & Patrizia Agostinis

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  1. Isabelle Coupienne
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  2. Grégory Fettweis
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  4. Patrizia Agostinis
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Correspondence to Jacques Piette.

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Coupienne, I., Fettweis, G., Rubio, N. et al. 5-ALA-PDT induces RIP3-dependent necrosis in glioblastoma. Photochem Photobiol Sci 10, 1868–1878 (2011). https://doi.org/10.1039/c1pp05213f

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