Raloxifene prevents stress granule dissolution, impairs translational control and promotes cell death during hypoxia in glioblastoma cells

Attwood, Kathleen M.; Robichaud, Aaron; Westhaver, Lauren P.; Castle, Elizabeth L.; Brandman, David M.; Balgi, Aruna D.; Roberge, Michel; Colp, Patricia; Croul, Sidney; Kim, Inhwa; McCormick, Craig; Corcoran, Jennifer A.; Weeks, Adrienne

doi:10.1038/s41419-020-03159-5

Cited by 22 publications

(20 citation statements)

References 68 publications

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“…Last, in glioblastoma cells, raloxifene, an estrogen receptor modulator, prevents SG dissolution, impairs protein synthesis control, and promotes cell death during hypoxia. Then, modulating SGs could be used to exploit the hypoxic niche of glioblastoma tumors ( Attwood et al, 2020 ).…”

Section: Stress Granules As Therapeutic Targets In Rna Virus Infection Cancer and Neurodegenerationmentioning

confidence: 99%

The Integral Role of RNA in Stress Granule Formation and Function

Campos-Melo

Hawley

Droppelmann

et al. 2021

Front. Cell Dev. Biol.

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Stress granules (SGs) are phase-separated, membraneless, cytoplasmic ribonucleoprotein (RNP) assemblies whose primary function is to promote cell survival by condensing translationally stalled mRNAs, ribosomal components, translation initiation factors, and RNA-binding proteins (RBPs). While the protein composition and the function of proteins in the compartmentalization and the dynamics of assembly and disassembly of SGs has been a matter of study for several years, the role of RNA in these structures had remained largely unknown. RNA species are, however, not passive members of RNA granules in that RNA by itself can form homo and heterotypic interactions with other RNA molecules leading to phase separation and nucleation of RNA granules. RNA can also function as molecular scaffolds recruiting multivalent RBPs and their interactors to form higher-order structures. With the development of SG purification techniques coupled to RNA-seq, the transcriptomic landscape of SGs is becoming increasingly understood, revealing the enormous potential of RNA to guide the assembly and disassembly of these transient organelles. SGs are not only formed under acute stress conditions but also in response to different diseases such as viral infections, cancer, and neurodegeneration. Importantly, these granules are increasingly being recognized as potential precursors of pathological aggregates in neurodegenerative diseases. In this review, we examine the current evidence in support of RNA playing a significant role in the formation of SGs and explore the concept of SGs as therapeutic targets.

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Section: Stress Granules As Therapeutic Targets In Rna Virus Infection Cancer and Neurodegenerationmentioning

confidence: 99%

The Integral Role of RNA in Stress Granule Formation and Function

Campos-Melo

Hawley

Droppelmann

et al. 2021

Front. Cell Dev. Biol.

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“…Typically, the identification of small molecules that can impede the interaction between crucial factors of RNP granules might be decisive for modulating their dynamics. In addition, designing strategies to identify key regulatory elements [126,127], or to evaluate new chemical entities, or even re-evaluate former ones [54,65,66,[128][129][130], is essential to identify potential targets and validate therapeutic options. Such small molecules could also have an unanticipated impact on immunotherapies, given the potential role of SGs in the expression of immune checkpoint ligands on cancer cells [131], and of inhibitory immune checkpoint receptors on lymphocytes [132].…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of the hypoxia-induced SG formation by the smallmolecule compounds β-estradiol, progesterone, and stanolone decreases the chemoresistance of human cervical cancer HeLa cells [65]. In addition, inhibiting the dissolution of hypoxia-induced SGs by the selective estrogen receptor modulator raloxifen reduces glioblastoma cell viability [66], indicating that the overall dynamics of SG assembly is important for cancer cell resistance. In chemoresistant gastric cancer cells, G3BP1-positive SGs sequestrate Bax mRNA encoding a proapoptotic factor [67].…”

Section: Open Accessmentioning

confidence: 99%

Cancer cell adaptability: turning ribonucleoprotein granules into targets

et al. 2021

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Stress granules (SGs) and processing bodies (P-bodies) are membraneless cytoplasmic condensates of ribonucleoproteins (RNPs). They both regulate RNA fate under physiological and pathological conditions, and are thereby involved in the regulation and maintenance of cellular integrity. During tumorigenesis, cancer cells use these granules to thrive, to adapt to the harsh conditions of the tumor microenvironment (TME), and to protect themselves from anticancer treatments. This ability to provide multiple outcomes not only makes RNP granules promising targets for cancer therapy but also emphasizes the need for more knowledge about the biology of these granules to achieve clinical use. In this review we focus on the role of RNP granules in cancer, and on how their composition and regulation might be used to elaborate therapeutic strategies. RNP granules between stress and translationRegulating the expression of the genomic information is crucial to ensure cell identity and functionality. During transformation into cancer cells and throughout tumor progression, cells dynamically modulate the expression of their genomic information to adapt to environmental cues. Control of mRNA translation ensures the spatiotemporal adjustment of protein synthesis, and is often dysregulated in cancer cells to favor their adaptability [1]. In particular, regulation of translation initiation allows cancer cells to reprogram this activity towards essential mRNAs, such as those encoding oncogenes, to facilitate cell growth, proliferation, and survival [2]. Moreover, cancer cells must adapt to stress conditions in the TME, mainly through activation of the integrated stress response (ISR) [3,4] (Figure 1). This pathway controls translation initiation through eukaryotic initiation factor 2 (eIF2), which, once phosphorylated on its α subunit, prevents the formation of the ternary complex (eIF2:GTP: methionyl-initiator-tRNA) and consequently blocks translation initiation [5]. Four stress-sensor kinases can induce eIF2α phosphorylation, namely the PKR-like endoplasmic reticulum kinase (PERK), general control nonrepressible 2 (GCN2), heme-regulated inhibitor (HRI), and protein kinase R (PKR). The outcome of ISR activation is a global decrease in protein synthesis, while sparing the translation of some specific mRNAs such as that of transcription factor ATF4 [4]. Activation of this pathway, and the resulting selective translation, favor tumor progression following endoplasmic reticulum stress caused for instance by the hypoxic TME [6]. Furthermore, ISR activation by aberrant MYC expression enables cancer cells to adapt to this intrinsic stress by reprogramming translational programs. Consequently, the ISR prevents cancer cells from entering apoptosis and promotes both tumor progression [7,8] and escape from antitumor immunity [9,10].

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“…Two well-known stress-induced phaseseparated messenger ribonucleoprotein (mRNP) granules are processing bodies (P-bodies) and stress granules (11,12). During stress, the direct connection between the formation of these granules coincident with an overall translational reduction suggests that the localization of mRNAs to these cytoplasmic granules might sequester the mRNAs away from the translational machineries, thus repressing the translation of the mRNAs (13)(14)(15)(16)). Yet how mRNAs are partitioned to or excluded from stress-induced granules remains unclear.…”

mentioning

confidence: 99%

Rvb1/Rvb2 proteins couple transcription and translation during glucose starvation

Chen

Tracy

Harjono

et al. 2021

Preprint

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During times of unpredictable stress, organisms must adapt their gene expression to maximize survival. Along with changes in transcription, one conserved means of gene regulation during conditions that quickly represses translation is the formation of cytoplasmic phase-separated mRNP granules such as P-bodies and stress granules. Previously, we identified that distinct steps in gene expression can be coupled during glucose starvation as promoter sequences in the nucleus are able to direct the subcellular localization and translatability of mRNAs in the cytosol. Here, we report that Rvb1 and Rvb2, conserved ATPase proteins implicated as protein assembly chaperones and chromatin remodelers, were enriched at the promoters and mRNAs of genes involved in alternative glucose metabolism pathways that we previously found to be transcriptionally upregulated but translationally downregulated during glucose starvation in yeast. Engineered Rvb1/Rvb2-binding on mRNAs was sufficient to sequester the mRNAs into phase-separated granules and repress their translation. Additionally, this Rvb-tethering to the mRNA drove further transcriptional upregulation of the target genes. Overall, our results point to Rvb1/Rvb2 coupling transcription, mRNA granular localization, and translatability of mRNAs during glucose starvation. This Rvb-mediated rapid gene regulation could potentially serve as an efficient recovery plan for cells after stress removal.

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Raloxifene prevents stress granule dissolution, impairs translational control and promotes cell death during hypoxia in glioblastoma cells

Cited by 22 publications

References 68 publications

The Integral Role of RNA in Stress Granule Formation and Function

The Integral Role of RNA in Stress Granule Formation and Function

Cancer cell adaptability: turning ribonucleoprotein granules into targets

Rvb1/Rvb2 proteins couple transcription and translation during glucose starvation

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