Glucocorticoids enhance chemotherapy-driven stress granule assembly and impair granule dynamics, leading to cell death

Abstract

Stress granules (SGs) can assemble in cancer cells upon chemotoxic stress. Glucocorticoids function during stress responses and are administered with chemotherapies. The roles of glucocorticoids in SG assembly and disassembly 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 and influence cell viability in cancer cells and in human-derived organoids. Cortisone augmented SG formation when combined with Vinorelbine (VRB). Live-cell imaging showed that cortisone increased SG assembly rates but reduced SG clearance rates after stress, by increasing protein residence times within the SGs. Mechanistically, 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 and reduced the population of cells trapped in mitotic catastrophe. These effects were mediated by G3BP1/2 core SG proteins. In conclusion, glucocorticoids induce SG assembly and cell death when administered with chemotherapies, suggesting that combining glucocorticoids with chemotherapies can enhance cancer cell chemosensitivity.

Utilizing flow cytometry sorting signal width to enrich for cells positive to endogenous gene integration of fluorescent proteins

“…To delineate signal that was restricted to the nucleus, the nuclear speckle protein 9G8 tagged with GFP was used (Figure 1A) [8, 9]. IGF2BP3 tagged with GFP was used to identify cytoplasmic signal (Figure 1B) [10]. Besides applying the standard forward and side scattering to select for singlet cells, we also measured the fluorescent signal along multiple dimensions (Figure 1A,B).…”

Activation of the mitochondrial unfolded protein response regulates the formation of stress granules

“…Several studies support a protective role for SGs, through impairing pro-apoptotic JNK signalling (Arimoto et al, 2008; Kitajima et al, 2023), sequestration of caspases (Fujikawa et al, 2023) or suppressing production of ROS (Park and Shin, 2023; Takahashi et al, 2013) and they have been described as “shock absorbers” dampening excessive innate immune response to viral infection (Paget et al, 2023). In contrast, persistent SGs are implicated in pro-death functions during chronic stress conditions as well as neurodegenerative diseases or tumour chemotherapy (Reineke et al, 2018; Reineke and Neilson, 2019; Schwed-Gross et al, 2022). Future studies will aim to the function of SGs formed during mitochondrial stress.…”

Stress granules: potential therapeutic targets for infectious and inflammatory diseases

“…However, it remains unclear whether inhibiting the expression of G3BP2 leads to a decrease in the formation of SGs, and the subsequent reduction in vascular inflammation levels during the process of atherosclerotic lesions. The anti-inflammatory drug cortisone can induce the production of SGs ( 151 ). Whether the powerful anti-inflammatory effects of cortisone are mediated by SGs will be a very interesting issue.…”