The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.

mTOR Signaling in Growth, Metabolism, and Disease

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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The Integral Role of RNA in Stress Granule Formation and Function.

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.

Cancer cell adaptability: turning ribonucleoprotein granules into targets.

The roles of G3BP1 in human diseases (review).

Stress granules (SGs) containing mRNAs and proteins stalled in translation during stress, are increasingly being implicated in disease and cancer including neurological disorders. The dysregulated assembly, persistence, disassembly and clearance of stress granules contribute to the process of senescence. Senescence has long been a mysterious player in cellular physiology and associated diseases. The systemic process of aging has been pivotal in the development of various neurological disorders like age-related neuropathy, Alzheimer's disease and Parkinson's disease. Glioma is a cancer of neurological origin with a very poor prognosis and high rate of recurrence, stress granules have only recently been implicated in its pathogenesis. Senescence has long been established to play an anti-tumorigenic role, however, relatively less studied is its pro-tumorigenic importance. Here, we have evaluated the existing literature to assess the crosstalk of the two biological phenomena of senescence and SG formation in the context of tumorigenesis. In this review we have attempted to analyze the contribution of senescence in regulating diverse cellular processes, like, senescence associated secretory phenotype (SASP), microtubular reorganization, telomeric alteration, autophagic clearance and how intricately these phenomena are tied with the formation of SGs. Finally, we propose that interplay between senescence, its contributing factors and the genesis of SGs can drive tumorigenicity of gliomas, which can potentially be utilised for therapeutic intervention. This article is protected by copyright. All rights reserved.

Role of stress granules in modulating senescence and promoting cancer progression: special emphasis on glioma

Glioblastoma (GBM) is the most common primary malignant brain tumor, and it has a uniformly poor prognosis. Hypoxia is a feature of the GBM microenvironment, and previous work has shown that cancer cells residing in hypoxic regions resist treatment. Hypoxia can trigger the formation of stress granules (SGs), sites of mRNA triage that promote cell survival. A screen of 1120 FDA-approved drugs identified 129 candidates that delayed the dissolution of hypoxia-induced SGs following a return to normoxia. Amongst these candidates, the selective estrogen receptor modulator (SERM) raloxifene delayed SG dissolution in a dose-dependent manner. SG dissolution typically occurs by 15 min post-hypoxia, however pre-treatment of immortalized U251 and U3024 primary GBM cells with raloxifene prevented SG dissolution for up to 2 h. During this raloxifene-induced delay in SG dissolution, translational silencing was sustained, eIF2α remained phosphorylated and mTOR remained inactive. Despite its well-described role as a SERM, raloxifene-mediated delay in SG dissolution was unaffected by co-administration of β-estradiol, nor did β-estradiol alone have any effect on SGs. Importantly, the combination of raloxifene and hypoxia resulted in increased numbers of late apoptotic/necrotic cells. Raloxifene and hypoxia also demonstrated a block in late autophagy similar to the known autophagy inhibitor chloroquine (CQ). Genetic disruption of the SG-nucleating proteins G3BP1 and G3BP2 revealed that G3BP1 is required to sustain the raloxifene-mediated delay in SG dissolution. Together, these findings indicate that modulating the stress response can be used to exploit the hypoxic niche of GBM tumors, causing cell death by disrupting pro-survival stress responses and control of protein synthesis.

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

While rare, post-ictal thoracolumbar burst fractures are commonly missed due to confounding factors, resulting in delayed treatment and the potential for serious neurological deficits. This paper serves as a call for a high-degree of clinical suspicion when treating post-ictal patients to ensure they undergo a focused neurological examination of the lower extremities. If unresponsive/uncooperative, spinal precautions should be maintained until the spine can be cleared clinically or radiographically. In all events, if the patient is complaining of musculoskeletal pain possibly originating from the spine, radiographic evaluations are warranted to prevent possible deficits caused by a missed thoracolumbar fracture.

Aaron Robichaud

Papers

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

Seizure-induced thoracolumbar burst fractures - Not to be missed.