Figure 7. Schematic diagram illustrating that PAI-1 secreted from radioresistant NSCLC cells induces paracrine signaling in radiosensitive NSCLC cells, leading to increased survival capacity and EMT phenotype.

In radioresistant NSCLC cells, PAI-1 is increased in response to cellular stresses such as irradiation, leading to increased extracellular PAI-1. The increased level of extracellular PAI-1 can interact with its receptor at the surface of radiosensitive NSCLC cells. After binding of PAI-1 to its receptor in radiosensitive NSCLC cells, cell survival and proliferation are induced by PAI-1-mediated AKT and ERK1/2 phosphorylation and caspase-3 inactivation. In addition, extracellular PAI-1 promotes EMT by regulating expression levels of EMT-related proteins, including Snail. This intercellular communication mediated by PAI-1 makes radiosensitive NSCLC cells more resistant to radiation.