57 - Séance principale
Oncology and metabolism
3 juin 2021, 17:35 - 19:05, Stream 4: Video Invited, SST, SSCViscérale & ARS
Low dose photodynamic therapy promotes endotheliale e-selectin expression in malignant pleural mesothelioma through NF-κB pathway activation
S. Cavin, L.-E. Chriqui, C. Gattlen, M. E. Ortolini, Y. Hao, M. Gonzalez, T. Krueger, E. Meylan, J. Y. Perentes, Presenter: L.-E. Chriqui (Lausanne)
In the pre-clinical setting, low-dose photodynamic therapy (L-PDT) was shown to enhance the immunogenicity of malignant pleural mesothelioma (MPM) through the induction of vascular endothelial E-selectin expression, a major adhesion molecule involved in leucocyte diapedesis. However, the underlying mechanisms of this observation remain unknown. Here we investigated the possibility that L-PDT-mediated E-selectin induction operates through canonical Nuclear Factor-Kappa B (NF-kB) signaling.
To assess the impact of L-PDT on canonical NF-ĸB pathway activation, we evaluated the expression of IκBα (total and phosphorylated) in endothelial EC-RC24 cell cultures treated with Visudyne© mediated L-PDT. Total protein content was extracted to perform Western blots at different timepoints ranging from 1 to 24 hours. In a second set of experiments, canonical NF-kB activation was blocked by using 2 different siRNAs that inhibit NEMO/IKKγ expression, an essential regulatory subunit of the IKK complex required for canonical NF-κB activation. We determined the expression levels of E-selectin in control or L-PDT-treated EC-RF24 cells. TNFα was used as positive control for NF-kB activation.
Increased phosphorylation of IκBα was observed from 3 to 12 hours after administration of a single L-PDT dose in endothelial cell monocultures while there was no change in the total amount of IκBα. L-PDT and TNFα treatment of endothelial cells caused E-selectin upregulation. L-PDT-mediated E-selectin induction was repressed in the presence of NEMO siRNAs.
L-PDT activates the NF-ĸB pathway in vascular endothelial cells, which induces E-selectin expression. The latter is thought to be essential for immune infiltration of MPM. Confirmation studies in vivo will help to comprehend and refine this therapeutic approach.