GLUCOCORTICOIDS ENHANCE CHEMOTHERAPY-DRIVEN STRESS GRANULE ASSEMBLY AND PROMOTE GRANULE RIGIDITY LINKED TO CELL DEATH

Stress granules (SGs) form in the cytoplasm when cells are subjected to different types of stress. For instance, SGs can assemble in cancer cells upon chemotoxic stress. Glucocorticoids function during stress responses and are administered with chemotherapies, however, their roles in SG assembly pathways are unknown. We examined whether combining glucocorticoids such as cortisone with chemotherapies from the vinca alkaloid family, that dismantle the microtubule network, will affect SG assembly and disassembly pathways, or will influence cell viability, in cancer cells and in human-derived organoids. Cortisone augmented SG formation when combined with chemotherapies in human cells, while alone it had no effect. Live-cell imaging showed that cortisone increased SG assembly rates but reduced their clearance rates after stress, by increasing protein, but not mRNA, residence times within the SGs. Mechanistically, both the chemotherapy Vinorelbine (VRB) and cortisone signaled through the eIF2α-mediated integrated stress response, yet induced different kinases, with cortisone activating the GCN2 kinase. Cortisone increased VRB-induced cell death that was mediated by the G3BP1/2 core SG proteins. In conclusion, glucocorticoids have an inducing effect on SG assembly and cell death when administered together with chemotherapies. Cortisone promotes the transition from pro-survival SGs to biophysically rigid pro-death SGs, suggesting that combining glucocorticoids with chemotherapies can enhance cancer cell chemosensitivity.