HomeENGLISH MAGAZINEMessenger RNAs: not just bare protein builders for oncology and neuroscience

Messenger RNAs: not just bare protein builders for oncology and neuroscience

Where mutation does not become a tumor: RNAs and neurons

Neuro-inflammation can worsen the outcomes of stroke, traumatic brain injury or spinal cord injury, as well as accelerate neurodegenerative diseases such as ALS, Parkinson’s, or Alzheimer’s. This suggests that limiting neuroinflammation may represent a promising new approach for the treatment of neurological diseases and neuropathic pain. Glial cells are the non-neuronal cells of the central nervous system or CNS, which help support and protect neurons. One of the types, microglia, are brain macrophages that respond to injury or infection. Microglia and astroglia are key cells of the central nervous system that, when activated, drive neuroinflammation by secreting toxic inflammatory mediators, including cytokines and chemokines. In a preclinical study published in the journal Glia, Professors Peter King and Burt Nabors, both of the University of Alabama at Birmingham’s Department of Neurology, show that their small molecule drug, SRI-42127, can potently attenuate triggers. of neuroinflammation. These experiments in glial cell cultures and mice now open the door to testing SRI-42127 in acute and chronic neurological injury models.

After 25 years of cooperation, their study builds on previous findings that microglia and astroglia cells rely on a key RNA-binding protein called HuR that protects messenger RNAs that code for inflammation mediators from degradation and promotes its translation into proteins. Neuroinflammation occurs when activated microglia and astrocytes in the brain or spine secrete cytokines and chemokines such as IL1β, IL-6, TNF-α, CXCL1, and CCL2. The messenger RNAs for those pro-inflammatory proteins contain elements rich in adenine and uridine, or AURE, which regulate their expression. Scientists have previously shown that HuR, an RNA regulatory protein that binds to AUREs, plays an important positive role in regulating the production of inflammatory cytokines. HuR normally concentrates in the glial cell nuclei. However, when glial cells are activated, HuR translocates out of the nucleus and into the cell cytoplasm, where it can increase the production of cytokines and chemokines. In previous researchers, UAB researchers have shown that HuR translocates out of the astrocyte nucleus in acute CNS disease, spinal cord injury and stroke.

They also showed that it translocates out of the nucleus into microglia in chronic CNS disease ALS or amyotrophic lateral sclerosis. Importantly, the HuR monomer cannot pass through the nuclear envelope which acts as a regulatory membrane barrier between the nucleus and the cytoplasm. Only HuR dimers (consisting of two single HuR molecules) are able to cross the nuclear membrane. This knowledge allowed the collaborative research of Southern Research, of Birmingham, Alabama and UAB, using a high-throughput screening, to identify a small molecule called SRI-42127 that inhibits HuR dimerization. Scientists used bacterial lipopolysaccharide (LPS) to activate glial cells and initiate the inflammatory cascade. They then found that treatment with SRI-42127 suppressed the translocation of HuR from the nucleus to the cytoplasm in LPS-activated glial cells, both in tissue culture and in mice. SRI-42127 also significantly attenuated the production of inflammatory mediators, such as IL-1β, IL-6, TNF-α, and the chemokines CXCL1 and CCL2. Furthermore, the compound suppressed microglia activation in the brains of mice and attenuated the recruitment of other immune cells outside the CNS.

Such entry of neutrophils and monocytes, mediated by the blood-brain barrier (BEE), can exacerbate inflammation in the brain or spinal cord. In summary, SRI-42127 penetrated the blood-brain barrier and rapidly suppressed neuroinflammatory responses. These findings underscore the pivotal role of HuR in promoting glial activation and the potential for SRI-42127 and other inhibitors of HuR to treat neurological diseases driven by this activation. “In a previously unpublished work in collaboration with Robert Sorge, PhD, associate professor in the Department of Psychology, UAB College of Arts and Sciences, Professors King and Nabors have discovered potential beneficial effects of SRI-42127 for reducing neuropathic pain, a condition that is triggered by microglia-induced neuro-inflammation. a non-opioid approach to treating pain. Overall this discovery opens universal doors to treating the neuroinflammation that underlies almost all modern neurodegenerative processes, such as Alzheimer’s, ischemic stroke, multiple sclerosis, ALS and all known neuropathies.

FrateRNAl creed: from neuroscience to cancer

In their long collaboration, King and Nabors used glioblastoma, a primary brain tumor, as a disease model to study HuR because many of the factors that drive neuroinflammation also promote glioblastoma growth. And this is where the link with cancer lies: Nabors focused on the oncosuppressive properties of SRI-42127 and its potential use in the treatment of glioblastoma and other cancers. One of the hallmarks of cancer is genomic instability, which is the tendency to accumulate mutations and damage to DNA that leads to alterations of the genome during cell division. DNA mutations can result from exposure to ultraviolet radiation or X-rays or from certain chemicals known as carcinogens; however, our cells have developed mechanisms to monitor and repair damaged DNA. The stability of the genome can also be threatened by the translation of some messenger RNAs (mRNAs). Some mRNAs are known to be associated with cancer metastases. To counter this threat, a specific protein, the heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1), binds these mRNAs and prevents them from making proteins.

Researchers at the Medical University of South Carolina have previously shown how hnRNP E1 binds to RNAs associated with metastases to inhibit their translation. hnRNP E1 binds RNA in the cell’s cytoplasm, but the protein is also found in the cell nucleus. This led the researchers to speculate that hnRNP E1 might also interact with DNA. Their results describe a novel role for hnRNP E1 in binding DNA in the nucleus. How hnRNP E1 binds and interacts with RNA has been extensively studied, but the discovery that hnRNP E1 also binds to DNA has opened up new avenues of research to explore. The DNA binding of hnRNP E1 is not limited to a few sites, but rather the protein has a plethora of potential binding sites, allowing it to detect or prevent DNA damage throughout the genome (a kind of sensor). The team also found that hnRNP E1 binds to a specific structure that can form on DNA known as motif I (I-motif), which forms in enriched regions in the cytosine nucleotide and acts as regulators of gene expression. Since DNA is formed by specific bonds between nucleotides, known as base pairs, numerous guanine bases are confronted with the cytosine-rich I-motifs.

These guanine-rich regions have the potential to form their own structure known as G-quadruplex (G4). G4s are present at the beginning of several oncogenes (tumor genes). However, it is not known whether I-motifs and G4 can exist simultaneously or if they are mutually exclusive.

Therefore, the binding of hnRNP to the regions of motif I could suppress the formation of G4 structures in order to protect the cell. Scientists hypothesized that hnRNP E1 would protect against genomic instability by maintaining I-motifs and suppressing G4. Indeed, experiments using cells that do not have hnRNP E1 simultaneously showed fewer I-motifs and more G4, DNA damage signals and mutations. Treating these cells with additional DNA-damaging agents, such as UV rays and hydroxyurea, resulted in an intensification of the cells’ DNA damage response that caused them to stop progressing through the cell cycle. These findings have great relevance in the field of cancer genetics and biology. Researchers have been studying the contribution of G4s to cancer biology for decades. Due to its association with oncogenes, these regions have been the target for drug design and anticancer therapies. Understanding the protein-DNA interactions that occur at sites opposite the G4s can contribute to the efficacy of these drugs, thus facilitating better targeting and specificity of drugs.

And the work is complicated, in light of the latest discovery made by UC San Francisco (USF) researchers, which offers clues to overcome resistance to drugs, such as tamoxifen, which are used in many types of breast cancer. The estrogen receptor α (ERα) drives over 70% of breast cancers. The new research found that in addition to its well-known activity in the nucleus, it may also help malignant cells overcome innate anticancer mechanisms and develop resistance to treatment. In the nucleus, ERα regulates the conversion of DNA to messenger mRNA. Once formed, the mRNA strand travels from the nucleus into the cytoplasm, where it instructs ribosomes to make proteins, a process known as translation. To their surprise, the researchers found that ERα also plays a role in this process by binding to the newly formed mRNA. Using breast cancer cell lines, the research team saw how ERα tends to bind to RNAs, particularly mRNAs involved in cancer progression. Some of these mRNAs prevent cells from committing suicide when they accumulate too many harmful mutations. Others help them proliferate in difficult conditions, such as a lack of oxygen or nutrients or the presence of chemotherapy drugs.

Endocrine therapies, such as tamoxifen, block the transcription activity of ERα in the nucleus of a cancer cell. Although they may initially be highly effective for most patients with ERα-positive breast cancer, a significant number develop resistance to the drug. To understand the role of ERα in this, the USF team led by Professor Ruggero analyzed the cancer cells of 14 patients diagnosed with ERα-positive breast cancer and found that they had high levels of target ERα mRNA. Then they tested breast cancer cell lines that had acquired resistance to tamoxifen, both in tissue cultures and in mouse xenografts. Inhibition of the RNA-ERα interaction restored the potency of tamoxifen against tumors in mice, making cultured cells more sensitive to stress and apoptosis (programmed cell death). A better understanding of the many functions of ERα, therefore, could help optimize current treatments, such as tamoxifen, as well as lead to new therapeutic goals. Compounds that target translational control in cancer are already in the clinic and can now be tested for potency against ERα-associated breast cancers.

  • edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Huang XT et al. Cancer Lett. 2021 Oct 10; 518:196-206.

Chellappan R, Guha A et al. Glia 2021 Sept 17 preprint.

Mohanty BK et al. Life Sci Allian 2021; 4(9):e202000995

Xu Y et al. Cell 2021 Sep 18: S0092-8674(21)01047-3.

Varshney D et al. Nat Rev Mol Cell Biol 2020; 21: 459–74.

Giaginis C et al. Pathol Oncol Res. 2018; 24(3):631-40.

Tan S et al. J Biol Chem. 2017; 292(33):13551-13564.

Dott. Gianfrancesco Cormaci
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (leader of the R&D for the partnership CoFood s.r.l.) - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica e salute sui siti web salutesicilia.com, medicomunicare.it e in lingua inglese sul sito www.medicomunicare.com
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