Stress granules promote chemoresistance by triggering cellular quiescence

Abstract

Cells respond to cellular stress by forming stress granules, molecular condensates containing non-translating messenger ribonucleoproteins. Stress granules form during chemotherapy and promote cell survival and chemoresistance, although the mechanism of this effect is not understood. We provide several lines of evidence that stress granules enhance cell survival by promoting cellular quiescence. First, we see a correlation between spontaneous stress granule formation and cell-cycle exit under non-stress conditions. Second, cells deficient in proteins required for stress granule formation (G3BP1/2) are less likely to exit the cell cycle under non-stress, stress, and chemotherapeutic conditions. Third, rescuing stress granule formation in G3BP1/2 knockout cells restores the fraction of cycling cells to wild-type levels. Finally, cells with enhanced stress granule formation (ddx6 knockout cells) show an increased propensity to exit the cell cycle. These results suggest that stress granules are important regulators of cellular quiescence, which could enable the identification of new anti-chemoresistance therapies that target stress granules.

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

“…This seemingly controversial, contradictory behavior may be readily explained by the fact that melatonin is a “smart”, pleiotropic molecule that selects the most appropriate strategy to protect the host organism [ 604 , 605 , 606 , 607 ]. The assembly of SGs is one of the major mechanisms used by cancer cells to adapt and survive under inhospitable, toxic microenvironments [ 608 , 609 ], as well as developing resistance to anticancer therapies [ 610 ]. Melatonin is known for its anticancer features, acting as a “broad-based metabolic buffer” to tune the cancer microenvironment [ 415 ].…”

Identification of small molecule inhibitors of G3BP-driven stress granule formation

“…Stress granules are a specialized type of cytoplasmic RNP granule that have been widely used as an archetypal RNP granule to uncover fundamental principles of biomolecular condensation ( Molliex et al, 2015 ; Protter and Parker, 2016 ). Stress granules have been implicated in several disease states, including cancer, where they may promote tumor chemoresistance ( Gao et al, 2019 ; Khong et al, 2022 Preprint ; Lavalée et al, 2021 ), and neurodegeneration, where aberrant granule condensation may lead to pleotropic cellular defects and accrual of proteinaceous deposits ( Kim et al, 2013 ; Mathieu et al, 2020 ; Molliex et al, 2015 ; Wolozin and Ivanov, 2019 ; Zhang et al, 2018 ). Thus, targeting stress granules holds promise for therapeutic purposes ( Patel et al, 2022 ).…”

Identification of small molecule inhibitors of G3BP-driven stress granule formation

“…Stress granules are a specialized type of cytoplasmic RNP granule that have been widely used as an archetypal RNP granule to uncover fundamental principles of biomolecular condensation [6,7]. Stress granules have been implicated in several disease states, including cancer, where they may promote tumor chemoresistance [8][9][10], and neurodegeneration, where aberrant granule condensation may lead to pleotropic cellular defects and accrual of proteinaceous deposits [7,[11][12][13][14]. Thus, targeting stress granules holds promise for therapeutic purposes [15].…”