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Tumor Discovery RNA-protein complexes deregulated in cancer

are under development for addressing the GGGGCC molecule interactors of SG proteins 264,265 to modulate SG
repeat expansion in C9orf72, a mutation linked to ALS stability. 176,265 This strategy could help overcome cancer
and frontotemporal dementia. For instance, DB1273 resistance to environmental stress and chemotherapy.
promotes G-quadruplex formation, reducing RNA foci The eIF2α phosphorylation-induced SG assembly occurs
and dipeptide translation in a Drosophila model of the during chemotherapy and involves various serine/threonine
neurological disease derived from all three independent protein kinases, including GCN2, HRI, PKR, and PERK.
C9orf72 repeat expansion iPSC lines and Drosophila with Natural compounds such as psammaplysin F reduce
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adult‐onset ubiquitous expression of 36 G4C2 repeats phosphorylated eIF2α levels, while cannabidiol attenuates
which causes neurodegeneration due to arginine-rich the formation of SGs and BCs in glioblastoma. Similarly,
proteins. Recent work by Xiao et al. reviewed machine medium-chain fatty acids, such as lauric acid, lipoic acid,
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learning approaches for studying small molecules targeting and their amides, show inhibitory effects. Notably,
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RNAs and provided a list of FDA-approved drugs based lipoamide has been demonstrated to inhibit SGs. 277
on oligonucleotide technology. Their work highlighted Lipoamide reduces the formation of cytoplasmic FUS-
the potential of machine learning in identifying RNA linked SGs induced by arsenate and mitigates SG formation
structures and prospective structural targets for small triggered by mitochondrial electron transport chain
molecules. Moreover, Kim and Kim reviewed the inhibition and hyperosmotic stress. However, it does not
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current understanding of RNAs, including circRNAs, and affect SGs formed in response to heat shock or glycolysis
the therapeutic frontiers in targeting regulatory RNAs. 273 inhibition. This suggests that lipoamide functions as
In cell-specific pathways and responses, such as either an antioxidant or an inhibitor of specific BC forms.
chromatin foci formation, transcription activation, and Importantly, lipoamide selectively inhibits SGs without
DNA damage response, BC formation is essential and affecting other BCs, such as Cajal bodies, nucleoli, and
depends on liquid–gel phase separation. These MLOs can DNA damage foci. 277
be targeted by small molecules that block protein domains. BCs can be targeted through three primary mechanisms.
One such BC target is the nuclear speckle, demonstrated The first involves targeting the driver components,
by the use of diphenylfuran to target MALAT1. i.e., proteins and nucleic acids, to downregulate or inactivate
Regarding the relationship between BCs and cancer, them. The second focuses on disrupting physicochemical
notable work has been conducted on the splicing factor interactions essential for BC formation involving proteins
ZMAT2. This protein contains two disordered regions and nucleic acids. The third strategy involves stabilizing or
critical for the formation of spliceosome complex destabilizing condensates using drugs that partition into
condensates and regulates the expression of the tripartite a BC, thereby modulating its activity. Table 6 provides
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motif protein 28 (TRIM28), 274,275 also known as Krüppel- a summary of the inhibitors discussed in this section
Associated Box (KRAB)-Associated Protein 1 (KAP1). (Table 6).
TRIM28 is a SUMOylation and RING-type ubiquitin-E3 Arsenic compounds, such as sodium arsenite, play a role
ligase involved in the degradation of programmed cell death in oxidative stress-induced SG formation, in which DDX3
ligand 1 (PD-L1), thereby modulating immunosuppression acetylation is involved. Arsenic trioxide (ATO), a highly
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in cancers. Targeting immune checkpoints has become a toxic compound, has been used to induce PML-RARα
focus in cancer therapy. Verteporfin, for example, inhibits degradation and inhibit PML nuclear bodies, particularly
PD-L1 expression through Golgi-related autophagy in PML-RARα translocation. Arsenite and ATO exhibit a
mechanisms, interfering with the interaction of TRIM28 dual role in paraspeckle formation, depending on the dose
with interferon regulatory factor 1 and blocking PD-L1 and duration of application. ATO promotes the formation
induction. ZMAT2 also has RNA-binding activity and of speckles and processing bodies by inducing spliceosome
promotes phase transition, playing a role in the maturation activity, induces SGs, and inhibits PML bodies by degrading
of TRIM28 mRNA during the formation of protein- PML-RARα. Trisenox was approved in 2002 as a drug for
nucleic acid condensates. By upregulating TRIM28, this the treatment of multiple myeloma (MM). In 2004, the FDA
process reduces ROS accumulation in HCC and supports approved its use for hepatocellular carcinoma therapy, and
cell proliferation. Finally, SGs, as previously discussed, in 2018, the combination of Trisenox/Tretinoin was also
contribute to cancer cells’ resistance to chemotherapy. approved. In addition, a phase II clinical trial in patients
Pharmacological inhibition of DDX3 has been shown to with refractory peripheral T-cell lymphoma (rPTCL)
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attenuate SG assembly. Consequently, small compounds demonstrated the antitumor activity of darinaparsin, an
targeting protein interactions and specific G3BP domains organic arsenical compound comprising dimethylated
could be used in combination with novel drugs and small arsenic conjugated to glutathione. 278

Volume 3 Issue 4 (2024) 20 doi: 10.36922/td.4657