Abstract
Introduction: Malignant pleural effusion (MPE) is primarily an immune-mediated manifestation of pleural-metastasized cancers, particularly adenocarcinomas that harbour KRAS mutations (ΔKRAS).We have previously determined that NF-κΒ activation in pleural tumor cells drives MPE formation, but the NF-κΒ pathways involved are obscure.
Aims and objectives: To investigate the mechanisms of NF-κB activation in pleural tumor cells that leads to MPE development.
Methods: We profiled baseline and host-induced NF-κB activity of mouse and human tumor cells, and examined its relationship with KRAS status. We further silenced NF-κB activating kinases aiming to eliminate endogenous and inducible NF-κB activity of mouse and human tumors.
Results: Tumor cells bearing KRAS mutations, competent of causing MPE, displayed IL-1β-induced IKKα translocation to the nucleus that was lost when KRAS knockdown was performed. In contrast, cell lines with wt KRAS that do not cause MPE did not respond to IL-1β with nuclear IKKα shuttling. shRNA IKKα, but not IKKβ, silencing of ΔKRAS tumors severely hampered their ability for MPE formation. IKKαoverexpression in wt KRAS tumors failed to restore the MPE-competent phenotype of ΔKRAS tumors, suggesting an addiction of IKKα withΔKRASin the tumor cell during MPE development. Furthermore, IL-1β, but not TNFα, originated from host immune cells was required to sustain the MPE-competent phenotype of IKKα-addicted KRAS-mutant tumors.
Conclusions: We demonstrate that KRAS-mutant tumor cells require host-IL-1β signaling for MPE precipitation. This phenotype is mediated by IKKα and not IKKβ.
This study was supported by a European Research Council Starting Independent Investigator Grant (#260524).
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