Differential transcriptome response to proton versus X-ray radiation reveals novel candidate targets for combinatorial PT therapy in lymphoma.

Abstract Background and Purpose Knowledge of biological responses to proton therapy (PT) in comparison to X-ray remains in its infancy. Identification of PT specific molecular signals is an important opportunity for the discovery of biomarkers and synergistic drugs and improved PT clinical usage. As PT can be used for lymphoma treatment, we study here lymphoma cell lines transcriptomic response to PT vs X-ray to identify potential drugable target. Materials and Methods Two different human (BL41) and murine (J3D) lymphoma cell lines were irradiated X-ray and PT. Differential transcriptome regulation was evaluated by RNA sequencing for each radiation type at 12 hours post irradiation. Gene-set enrichment analysis was used to discover potentially deregulated molecular pathways and potential targets for lymphoma cells sensitization to PT. Results Transcriptomic. Gene set enrichment analyses discovered pathways that contribute to the unfold protein response and mitochondrial transport. Functional validation showed increased UPR activation and decreased protein translation perhaps due to increased oxidative stress and oxidative protein damage after PT. PPARgamma was identified as a potential regulator of PT transcriptomic response. Inhibition of PPARgamma by T0070907 and SR2595 compounds sensitized lymphoma cells to PT. Conclusions Proton vs X-ray led to the transcriptional deregulation of a specific subset of genes that is functionally in line with diminished protein translation, UPR activation and increased oxidative stress. This study demonstrates that radiation types trigger distinct molecular responses in lymphoma cells and identifies PPARgamma inhibition as a potential strategy for sensitization of lymphoma to PT