40 research outputs found
Ribosomopathies and cancer. Pharmacological implications
No full textIntroduction: The ribosome is a ribonucleoprotein organelle responsible for protein synthesis, and its biogenesis is a highly coordinated process that involves many macromolecular components. Any acquired or inherited impairment in ribosome biogenesis or ribosomopathies is associated with the development of different cancers and rare genetic diseases. Interference with multiple steps of protein synthesis has been shown to promote tumor cell death.
Areas covered: We discuss the current insights about impaired ribosome biogenesis and their secondary consequences on protein synthesis, transcriptional and translational responses, proteotoxic stress, and other metabolic pathways associated with cancer and rare diseases. Studies investigating the modulation of different therapeutic chemical entities targeting cancer in in vitro and in vivo models have also been detailed.
Expert opinion: Despite the association between inherited mutations affecting ribosome biogenesis and cancer biology, the development of therapeutics targeting the essential cellular machinery has only started to emerge. New chemical entities should be designed to modulate different checkpoints (translating oncoproteins, dysregulation of specific ribosome-assembly machinery, ribosomal stress, and rewiring ribosomal functions). Although safe and effective therapies are lacking, consideration should also be given to using existing drugs alone or in combination for long-term safety, with known risks for feasibility in clinical trials and synergistic effects
An intricate rewiring of cancer metabolism via alternative splicing
No full textAll human genes undergo alternative splicing leading to the diversity of the proteins. However, in some cases, abnormal regulation of alternative splicing can result in diseases that trigger defects in metabolism, reduced apoptosis, increased proliferation, and progression in almost all tumor types. Metabolic dysregulations and immune dysfunctions are crucial factors in cancer. In this respect, alternative splicing in tumors could be a potential target for therapeutic cancer strategies. Dysregulation of alternative splicing during mRNA maturation promotes carcinogenesis and drug resistance in many cancer types. Alternative splicing (changing the target mRNA 3'UTR binding site) can result in a protein with altered drug affinity, ultimately leading to drug resistance.. Here, we will highlight the function of various alternative splicing factors, how it regulates the reprogramming of cancer cell metabolism, and their contribution to tumor initiation and proliferation. Also, we will discuss emerging therapeutics for treating tumors via abnormal alternative splicing. Finally, we will discuss the challenges associated with these therapeutic strategies for clinical applications
Alternative Splicing: A Potential Therapeutic Target in Hematological Malignancies
No full textLeukemia represents the most prevalent malignancy in children, constituting 30% of childhood cancer cases, with acute lymphoblastic leukemia (ALL) being particularly heterogeneous. This paper explores the role of alternative splicing in leukemia, highlighting its significance in cancer development and progression. Aberrant splicing is often driven by mutations in splicing-factor genes, which can lead to the production of variant proteins that contribute to oncogenesis. The spliceosome, a complex of small nuclear RNAs and proteins, facilitates RNA splicing, a process critical for generating diverse mRNA and protein products from single genes. Mutations in splicing factors, such as U2AF1, SF3B1, SRSF2, ZRSR2, and HNRNPH1, are frequently observed across various hematological malignancies and are associated with poor prognosis and treatment resistance. This research underscores the necessity of understanding the mechanisms of RNA splicing dysregulation in order to develop targeted therapies to correct these aberrant processes, thereby improving outcomes for patients with leukemia and related disorders
P53: A key player in diverse cellular processes including nuclear stress and ribosome biogenesis, highlighting potential therapeutic compounds
No full textThe tumor suppressor proteins are key transcription factors involved in the regulation of various cellular processes,such as apoptosis, DNA repair, cell cycle, senescence, and metabolism. The tumor suppressor protein p53 responds to different type of stress signaling, such as hypoxia, DNA damage, nutrient deprivation, oncogene activation, by activating or repressing the expression of different genes that target processes mentioned earlier. p53 has the ability to modulate the activity of many other proteins and signaling pathway through protein–protein interaction, post-translational modifications, or non-coding RNAs. In many cancers the p53 is found to be mutated or inactivated, resulting in the loss of its tumor suppressor function and acquisition of new oncogenic properties. The tumor suppressor protein p53 also plays a role in the development of other metabolic disorders such as diabetes, obesity, and fatty liver disease. In this review, we will summarize the current data and knowledge on the molecular mechanisms and the functions of p53 in different pathways and processes at the cellular level and discuss the its implications for human health and disease
Advances in molecular function of UPF1 in Cancer
No full textIt is known that more than 10% of genetic diseases are caused by a mutation in protein-coding mRNA (premature termination codon; PTC). mRNAs with an early stop codon are degraded by the cellular surveillance process known as nonsense-mediated mRNA decay (NMD), which prevents the synthesis of C-terminally truncated proteins. Up-frameshift-1 (UPF1) has been reported to be involved in the downregulation of various cancers, and low expression of UPF1 was shown to correlate with poor prognosis. It is known that UPF1 is a master regulator of nonsense-mediated mRNA decay (NMD). UPF1 may also function as an E3 ligase and degrade target proteins without using mRNA decay mechanisms. Increasing evidence indicates that UPF1 could serve as a good biomarker for cancer diagnosis and treatment for future therapeutic applications. Long non-coding RNAs (lncRNAs) have the ability to bind different proteins and regulate gene expression; this role in cancer cells has already been identified by different studies. This article provides an overview of the aberrant expression of UPF1, its functional properties, and molecular processes during cancer for clinical applications in cancer. We also discussed the interactions of lncRNA with UPF1 for cell growth during tumorigenesis
Ribosome-directed therapies in cancer
No full textThe human ribosomes are the cellular machines that participate in protein synthesis, which is deeply affected during cancer transformation by different oncoproteins and is shown to provide cancer cell proliferation and therefore biomass. Cancer diseases are associated with an increase in ribosome biogenesis and mutation of ribosomal proteins. The ribosome represents an attractive anti-cancer therapy target and several strategies are used to identify specific drugs. Here we review the role of different drugs that may decrease ribosome biogenesis and cancer cell proliferation
Ribosomal protein RpL35/uL29 Function in Different Diseases
No full textRpL35/uL29 is member of large subunits. It is shown that RpL35/uL29 participate in different processes in diseases and development. It is shown that RpL35/uL29 is important for ribosome mature. Many authors show that RpL35/uL29 is good indicator for diagnosis. Here we will described role and function of ribosomal protein RpL35/uL29 in different cancer diseases such as colorectal adenocarcinoma and atherosclerosis
OXIDATIVE STRESS EFFECT IN RIBOSOMAL BIOGENESIS IN CANCER CELLS
No full textOxidative stress is a condition where the levels of reactive oxygen species (ROS) exceed the normal level on the cell’s antioxidant defenses. Oxidative stress can cause damage of the DNA, proteins, and lipids. Ribosome biogenesis is the process of making ribosomes. Ribosome biogenesis involves the transcription, processing, and assembly of ribosomal RNA (rRNA) and ribosomal proteins (r-proteins) into functional ribosomal subunits. Cancer is a disease characterized by uncontrolled cell growth, invasion, and metastasis. Cancer cells often have increased levels of oxidative stress and ribosome biogenesis, which can promote their survival, adaptation, and proliferation in the tumor microenvironment. In this review, we discuss how oxidative stress can have different effects on ribosome biogenesis in cancer cells, depending on the type, severity, and duration of the stress, as well as the genetic and epigenetic characteristics of the cells
Immunotherapy in Childhood Acute Lymphoblastic Leukemia
No full textAcute lymphoblastic leukemia (ALL) is known as a heterogeneous disease. The progress is possible to make in understanding of biological mechanism who play pivotal role in the development of therapies. Here I will try to summarize the current and future possibilities of management of adult and children ALL. Many inhibitors are used to inhibit tyrosine kinase, chimeric antigen receptor and gene therapy for cure of ALL. The FDA has approved a number of drugs for treatment of children who are sick from ALL. Currently, is known that long term of survival is achieved in more than 50% of patients with B-ALL, 50-60% T-ALL, and 80% mature ALL. In era of precision medicine, the future is based in using of less cytotoxic and based and more target agents
Anti-SARS-coronavirus treatment based on molecular interaction
No full textSARS-CoV-2 belongs the family betacoronavirus in Coronoviridae; it is known to have single strand RNA which is enveloped. The first case is reported late2019 in China. From there it is circulate around the world, causing the COVID-19 pandemic situation with higher fatality rates. At the beginner of April 2021 SARS-CoV-2 has infected more than 130 million people and led to 2.84 million death. There are several strategies for cure of SARS-CoV-2 infection, to date the number of drugs who are used for treatment is increased depends of these drugs are used alone or in combination form. FDA has approved remedesivir who have the ability to neutralized antibodies, although clinical effects were controversial. Here we discuss for development of new strategies for therapeutic reason in patients infected by SARS-CoV-2
