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Tumor Discovery RNA-protein complexes deregulated in cancer

Paraspeckle disintegration has been achieved using eIF2α phosphorylation, ER stress from unfolded protein
DNA intercalators. Actinomycin D (ActD) binds to the retention, thapsigargin, and arsenite (an SG inducer).
DNA minor groove, promoting paraspeckle disassembly Notably, P bodies remain functional and unaffected by
and resulting in smaller condensates. While ActD ISRIB treatment or stressors. ISRIB increases the activity
administration reduces the size of NEAT1_2 speckles, it of eIF2B, eIF5, and other initiation factors by directly or
does not alter their number. Meanwhile, core paraspeckle indirectly reversing the effects of phosphorylated eIF2α.
proteins SFPQ and NONO remain localized to the It acts as a molecular glue, linking eIF2B tetramers to
perinucleolar caps. decameric active enzymes.
Because DNA-binding molecules can induce double- A hollow nanoparticle-based delivery system
strand breaks, it has been demonstrated that paraspeckle was developed for ISRIB. PEGylated copper sulfide
disintegration is not linked to DNA damage or RNA nanoparticles (HCuS NPs) encapsulating ISRIB, combined
polymerase inhibition. An increase in smaller NEAT1_2 with phase-change material lauric acid (LA), were used in
paraspeckles was observed following treatment with photothermal therapy (PTT). This light-controlled ISRIB
etoposide, a topoisomerase II inhibitor, and flavopiridol, release inhibited SG formation during PTT, enhancing
an inhibitor of cyclin-dependent kinases. In contrast, the the antitumor effect and inducing immunogenic cell
microtubule inhibitor vincristine had no effect, as it does death (ICD). In addition, a pH-driven and NIR photo-
289
not bind to dsDNA. 285
responsive smart drug delivery system (IL@H-PP)
The structural basis of double-stranded DNA helix promoted the production of ROS by tumor-associated
binding underpins the assembly and maintenance of macrophages (TAMs). TAMs were repolarized toward an
paraspeckles, speckles, and other nuclear ncRNA-based M1 phenotype, remodeling the tumor microenvironment
condensates. This insight opens new avenues for studying from immunosuppressive to immunity-competent.
the mechanisms of drugs such as etoposide, actinomycin D, ISRIB has demonstrated therapeutic potential beyond
and mithramycin A, which are widely used in osteosarcoma cancer treatment. It has shown promise in addressing
treatment. Targeting P bodies also holds potential for pulmonary veno-occlusive disease, Fragile X syndrome,
cancer therapy. A recent review discussed the therapeutic neurodegenerative disorders associated with SG formation,
implications of modulating P body formation. 184,286,287 eIF2α phosphorylation, and cognitive impairment. 289,290
Hyperphosphorylation of eIF2a enhances the anticancer Inhibition of the ISR has also been explored for the
activity of bortezomib by eradicating quiescent cancer treatment of diseases beyond cancer. In lysosomal storage
cells and inhibiting their survival. Under ER stress, the disorders, two compounds (patent U.S. Ser. No. 63/675,391)
transmembrane protein kinase/endoribonuclease inositol- have been found to enhance glucocerebrosidase function
requiring enzyme 1 (IRE1) is activated, clustering into in Gaucher patient-derived fibroblasts through an MiT/
ER membrane-bound condensates associated with SGs. TFE transcription factor that promotes lysosomal gene
IRE1α clusters tether SGs to the ER in response to various translation. An ISR antagonist was combined with a
stressors. This clustering facilitates the splicing of XBP1 PIKfyve (FYVE finger-containing phosphoinositide
mRNA to produce the XBP1 isoform 2, which is involved in kinase) modulator to improve cellular glucocerebrosidase
the unfolded protein response. Diseases linked to XBP1 activity. This combination likely succeeded because ISR
288
dysfunction include bipolar disorders, B-cell lymphomas, signaling appears to be slightly activated by treatment with
and leukemias. XBP1 is frequently overexpressed in BCs either of these small molecules individually. 291
and metastatic malignancies. MG132, a proteasome
inhibitor, has been shown to activate GCN2. 5. Application of emerging technologies in
BC studies
The integrated stress response (ISR) inhibitor, ISRIB
(M7425, AbMole, Huston, USA), is a selective small The potential of RNA to adopt diverse structures within
molecule inhibitor of eukaryotic translation initiation or outside condensates can be utilized for innovative
factor 2-alpha kinase 3, also known as protein kinase R therapeutic purposes. This includes enzymatic RNA
(PKR)-like ER kinase (PERK) signaling. ISRIB effectively molecules, known as ribozymes, exhibiting activity
reverses eIF2α phosphorylation and disassembles SGs. exclusively within condensates. These structures influence
When administered to be stressed cells with preformed SGs, RNA–RNA interactions, affecting the material properties
ISRIB induces their rapid disassembly, releasing mRNAs of RNA-seeded condensates and impacting RNA sorting
into the RNA pool for active translation. ISRIB reverses during the development of phase-separated assemblies.
the translational inhibition caused by stress and eIF2α Analyzing RNA structures in dense phases and the
phosphorylation. ISRIB prevents SG formation induced by supramolecular formations within them poses significant

Volume 3 Issue 4 (2024) 24 doi: 10.36922/td.4657