Fig. 10

Proposed mechanism of genotoxic stress-mediated NPM release and extracellular NPM functions on hCmPCs. Following DSB formation caused either by Dox-induced nucleolar stress or UV light treatment, the nucleolus is rapidly disrupted and NPM is released from the nucleolus to the nucleoplasm, subsequently to the cytoplasm and then is rapidly secreted in the extracellular space by an active mechanism, that requires TLR4 activity and an autophagy mechanism. Our results show that NPM binds to TLR4 and activates a TLR4-dependent signalling cascade that causes NFkB translocation in the nucleus and the transcription of IL-6 and COX-2, thus causing inflammation. The extracellular NPM is also able to inhibit cell proliferation without induction of cell death. In conclusion, following genotoxic stress, NPM acts similarly to an alarmin in hCmPCs, being rapidly secreted and promoting cell cycle arrest and TLR4/NFκB-dependent inflammatory response