Stress granule: A promising target for cancer treatment

Abstract

Stress granules (SGs) are primarily composed of mRNAs that stall at translation initiation and usually appear in the cytoplasm under unusual physiological or pathological conditions such as hypoxia, oxidative stress, and viral infection. Recent studies have indicated that several components of SGs participate in tumourigenesis and cancer metastasis through tumour-associated signalling pathways as well as other mechanisms. Furthermore, some chemotherapy drugs have been reported to induce SGs.Thus, the roles of SGs in cancer treatment have attracted considerable interest.Importantly, disturbing the recruitment of SGs components or microtubule polymerization, as well as other strategies that can abolish SGs formation, is reported to inhibit tumour progression, suggesting that targeting SGs could be a promising strategy for cancer treatment. In this review, we summarize the relationship between SGs and cancer, as well as recent advances in targeting SGs, in the interest of providing new opportunities for cancer treatment. | INTRODUCTIONDuring the eukaryotic gene expression process, RNA translation is thought to be a key process that regulates RNA modification, stability, location, protein function, and chromatin structure (Rizvi & Smith, 2017). Stresses such as hypoxia, viral infection, heat shock, and oxidative stress can induce multiple tissue and organ damages, as well as disordered protein translation, all of which are called "integrated stress responses (ISRs)" (Anderson, Kedersha, & Ivanov, 2015). Composed of non-translated mRNAs, cytoplasmic messenger ribonucleoprotein particles (mRNPs) are components of the ISR and emerge when translation initiation is stalled, subsequently forming granules to ensure cell adaptation to stress conditions. These RNA granules can usually be divided into four types: processing bodies, stress granules (SGs), neuronal granules, and germ cell granules (Anderson & Kedersha, 2006). Among these granules, SGs are the most well studied. Given that SGs assemble when translation initiation is stalled, they usually occur in the cytoplasm, containing various RNA-binding proteins (RBPs), non-translated RNAs, types of translation initiation factors, poly(A)binding protein, and ribosomal subunits.SGs assemble immediately once stresses are encountered and are cleaned up once the stresses disappear (Reineke & Neilson, 2019).As SGs are a non-typical type of multifunctional membrane-less organelles, the formation of SGs is a highly regulated and dynamic process. SGs are usually triggered by the serine 51 phosphorylation of eukaryotic initiator factor 2A (eIF2A; Buchan & Parker, 2009;Gilks et al., 2004), which represents the initiation of 48-s ribosomal subunit disassembly and translation arrest. Considered to be one of the most pivotal components of SGs, the phosphorylation of Ras-GTPaseactivating protein SH3 domain-binding protein 1 (G3BP1) affects SG formation (Mahboubi & Stochaj, 2017). Moreover, the post-translation modifications (PTMs) of mRNPs components are also closely associated with SGs a...

Treatment of cancer cells with Lapatinib negatively regulates general translation and induces stress granules formation

“…This is consistent with our PERK depletion experiments showing that targeting PERK-SG pathway further sensitizes T47D to Lap and supporting a potential role of PERK-SG formation pathway in resistance of cancer cells to drug treatment. While these results are in line with the role of SG in antagonising cell death [38], they are consistent with the emerging role of PERK in the promotion of tumor growth and angiogenesis [39][40][41]. Although the contribution of SG in PERK-mediated tumor growth and angiogenesis remained to be established, our study described here suggests the formation of SG as a potential downstream effector of PERK in Lap resistance, an assumption that requires future in vivo studies using patient-derived xenografts and breast biopsies of cancer patients, to be validated.…”

Targeting stress granules: A novel therapeutic strategy for human diseases

“…2 ), including cancers, neurodegenerative diseases, viral infections and autoimmune disease, well-documented by elegant reviews [ [33] , [34] , [35] , [36] , [37] ]. SGs affect multiple pathways by intercepting and sequestering signalling components, such as RACK1 (p38/JNK signalling), TRAF2 (NF-κB signalling), Raptor (mTOR signalling) and RhoA/ROCK1 (Wnt signalling) [ [33] , [34] , [35] , [36] , [37] ]. When exposed to stress environments, cells may arrest the cell cycle and repair stress-induced damage, or proceed to apoptosis.…”

“…The tumour microenvironment is full of stresses, such as a high concentration of ROS, hypoxia and hypoglycaemia, which can strongly trigger SG formation. SGs are observed in many human cancers, such as pancreatic cancer, hepatocellular carcinoma, glioma/glioblastoma, sarcoma, mantle cell myeloma, colorectal cancer, head and neck cancers and prostate cancer [ 36 ]. SGs regulate the expression of oncogenes, tumour metabolism, and adapt tumour cells to the microenvironment, which are directly related to the development of tumours and the efficiency of anticancer drugs.…”

Stress Granule Formation Attenuates RACK1-Mediated Apoptotic Cell Death Induced by Morusin

“…SGs have long been proposed as a key molecular platform for the coordinate regulation of various pathways to reduce cancer cell death mediated by a wide range of stressors and drugs. For example, SGs are induced in multiple cancer cell lines by treatment of chemotherapeutic reagents targeting RNA synthesis including 5-fluorouracil and sorafenib, thereby suppressing the antitumor capacity of the drugs [23,50]. However, questions about the drug-specific mechanisms of SG assembly have not yet been addressed.…”