New role of tumor suppressor PML in the control of the NLRP3-dependent tumor growth

Promyelocytic Leukemia Protein (PML) is a multi-faceted protein, that can be present at nuclear level, where it plays pivotal roles in tumor growth, modulating a wide number of cell activities, including tumor suppression, anti-viral and anti-bacterial responses. Among its very numerous functions, PML can also localize to the ER-mitochondria contact sites (MAMs) where it can control several functions such as the transfer of calcium into the mitochondria, ROS production, apoptosis and autophagy. Recently, MAMs have been shown to function as a platform for inflammatory signaling regulated by the most widely characterized inflammasome, so-called NLRP3. At rest, the NLRP3 protein resides at the ER, whereas upon inflammation activation, both NLRP3 and its adaptor ASC redistribute to MAMs to permit inflammasome formation. Here we discover that the down-regulation of the tumor suppressor PML at the host level can drive an immune response that is able to worsen cancer instead of ameliorate it, enhancing the process of IL-1β release. In particular, we found that the crosstalk between PML and the NLRP3 inflammasome at the ER/MAMs compartments exist and we demonstrated how this molecular pathway in the host could impact cancer development. Furthermore, we revealed that genetic or pharmacological manipulation of NLRP3-inflammasome and of one of its activator, the P2X7 receptor, have the benefit of blocking the release of IL-1β in a PML KO background, reducing tumor growth. It is well known that even anti-cancer therapies, like radio- and chemotherapy, are able to trigger an immune response. Traditional research on radiotherapy (RT) is focused on increasing treatment doses to target volume and reducing treatment fields to spare healthy tissues. However, radiations interact actively with host’s immune system contributing strongly to limit tumor progression. There is some evidence that RT inflammation is related to activation of inflammasome determining an increase of interleukins (IL): IL-1β and IL-18. We demonstrate that low ...