The IRE1 Inhibitor KIRA6 Curtails The Inflammatory Trait Of Immunogenic Anticancer Treatments By Targeting HSP60 Independent Of IRE1
Rufo, N.; Korovesis, D.; van Eygen, S.; Derua, R.; Garg, A. D.; Finotello, F.; Vara Perez, M.; Rozanc, J.; Dewaele, M.; de Witte, P. A.; Alexopoulos, L.; Janssens, S.; Sinkkonen, L.; Sauter, T.; Verhelst, S. H. L.; Agostinis, P.
Show abstract
Cellular stress evoked by immunogenic anticancer treatments engaging the unfolded protein response (UPR) can elicit inflammation with conflicting therapeutic outcomes. To define cell-autonomous mechanisms coupling the UPR to molecular mediators of inflammation, we profiled the transcriptome of cancer cells responding to immunogenic or weakly immunogenic-treatments. Bioinformatics-driven pathway analysis indicated that immunogenic treatments instigated NF-{kappa}B/AP-1-inflammatory pathways, which were abolished by the IRE1-kinase inhibitor KIRA6. Cell-free fractions of chemotherapy and KIRA6 co-treated cancer cells were deprived of pro-inflammatory/chemoattractant factors and failed to mobilize innate immune cells. Strikingly, these potent KIRA6 anti-inflammatory effects were found to be independent of IRE1. Generation of a KIRA6-clickable photoaffinity probe, mass spectrometry and co-immunoprecipitation analysis identified cytosolic HSP60 as a KIRA6 off-target in the NF-{kappa}B pathway. In sum, our study unravels that inflammation evoked by immunogenic treatments is curtailed by KIRA6 independently of IRE1 and further suggests great caution in interpreting the anti-inflammatory action of IRE1 chemical inhibitors.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- PARP1 inhibitors trigger innate immunity via PARP1 trapping-induced DNA damage response 95%
- Oxygen levels at the time of activation determine T cell persistence and immunotherapeutic efficacy 95%
- The transcriptomic response of cells to a drug combination is more than the sum of the responses to the monotherapies 94%
Similar papers in this journal
- Prolonging lung cancer response to EGFR inhibition by targeting the selective advantage of resistant cells 95%
- Bone morphogenetic protein (BMP) signaling determines neuroblastoma cell fate and sensitivity to retinoic acid. 94%
- Phosphoproteome profiling uncovers a key role for CDKs in TNF signaling 94%
Similar papers in this journal
- TSG101 Associates with PARP1 and is Essential for PARylation and DNA Damage-induced NF-κB Activation 94%
- Reprogrammed mRNA translation drives resistance to therapeutic targeting of ribosome biogenesis 93%
- A novel IKK- and proteasome-independent mechanism of RelA activation triggers senescence associated secretome via transcriptional repression of NFKBIA 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.