Lipid metabolism and cancer Bian, Xueli; Liu, Rui; Meng, Ying ...
The Journal of experimental medicine,
2021-Jan-04, Letnik:
218, Številka:
1
Journal Article
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Dysregulation in lipid metabolism is among the most prominent metabolic alterations in cancer. Cancer cells harness lipid metabolism to obtain energy, components for biological membranes, and ...signaling molecules needed for proliferation, survival, invasion, metastasis, and response to the tumor microenvironment impact and cancer therapy. Here, we summarize and discuss current knowledge about the advances made in understanding the regulation of lipid metabolism in cancer cells and introduce different approaches that have been clinically used to disrupt lipid metabolism in cancer therapy.
Clustered regularly interspaced short palindromic repeats (CRISPR), CRISPR interference and programmable base editing have transformed the manipulation of eukaryotic genomes for potential therapeutic ...applications
. Here, we exploited CRISPR interference and programmable base editing to determine their potential in editing a TERT gene promoter-activating mutation, which occurs in many diverse cancer types, particularly glioblastoma
. Correction of the -124C>T TERT promoter mutation to -124C was achieved using a single guide RNA (sgRNA)-guided and catalytically impaired Campylobacter jejuni CRISPR-associated protein 9-fused adenine base editor (CjABE). This modification blocked the binding of members of the E26 transcription factor family to the TERT promoter, reduced TERT transcription and TERT protein expression, and induced cancer-cell senescence and proliferative arrest. Local injection of adeno-associated viruses expressing sgRNA-guided CjABE inhibited the growth of gliomas harbouring TERT-promoter mutations. These preclinical proof-of-concept studies establish the feasibility of gene editing as a therapeutic approach for cancer and validate activated TERT-promoter mutations as a cancer-specific therapeutic target.
Triglyceride–glucose index (TyG index) has been used in healthy individuals as a marker of insulin resistance. Type 2 diabetes mellitus (T2DM) showed an increased risk of developing low muscle mass ...compared to control subjects. This study is performed to determine the association of TyG index with the presence of low muscle mass in T2DM patients. This study included 1098 T2DM patients who were recruited from the inpatients in Qilu Hospital (Qingdao). Skeletal muscle index (SMI) was measured using dual energy X-ray absorptiometry. Serum triglyceride and fasting plasma glucose were measured and used to calculate TyG index. 119 male subjects (20.2%) had low muscle mass, while 72 female subjects (14.1%) had low muscle mass in T2DM patients. TyG index was correlated with a decreased risk of low muscle mass in both male and female T2DM groups. TyG index was found to be positively correlated with SMI after multivariate adjustment in male subjects. When TyG index was ≤ 9.5, TyG index was positively correlated with SMI. However, when TyG index was > 9.5, there was not a significant association between TyG index and SMI. Moreover, TyG index was not correlated with SMI after multivariate analysis in female subjects. However, TyG index was positively correlated with SMI when TyG index was ≤ 9. When TyG index was > 9, TyG index was negatively correlated with SMI, however, the correlation was not statistically significant. TyG index is inversely correlated with the presence of low muscle mass in T2DM patients.
Tumor-specific pyruvate kinase M2 (PKM2) is essential for the Warburg effect. In addition to its well-established role in aerobic glycolysis, PKM2 directly regulates gene transcription. However, the ...mechanism underlying this nonmetabolic function of PKM2 remains elusive. We show here that PKM2 directly binds to histone H3 and phosphorylates histone H3 at T11 upon EGF receptor activation. This phosphorylation is required for the dissociation of HDAC3 from the CCND1 and MYC promoter regions and subsequent acetylation of histone H3 at K9. PKM2-dependent histone H3 modifications are instrumental in EGF-induced expression of cyclin D1 and c-Myc, tumor cell proliferation, cell-cycle progression, and brain tumorigenesis. In addition, levels of histone H3 T11 phosphorylation correlate with nuclear PKM2 expression levels, glioma malignancy grades, and prognosis. These findings highlight the role of PKM2 as a protein kinase in its nonmetabolic functions of histone modification, which is essential for its epigenetic regulation of gene expression and tumorigenesis.
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► PKM2 binds to and phosphorylates H3-T11 ► PKM2-dependent H3-T11 phosphorylation is required for H3-K9 acetylation ► H3-T11 phosphorylation is required for gene expression and tumorigenesis ► H3-T11 phosphorylation levels correlate with glioma malignancy and prognosis.
A kinase best known as a regulator of glycolysis doubles as a histone kinase to promote oncogenic gene expression.
Age-related cardiovascular disease is the leading cause of death in elderly populations. Coxibs, including celecoxib, valdecoxib, etoricoxib, parecoxib, lumiracoxib, and rofecoxib, are selective ...cyclooxygenase-2 (COX-2) inhibitors used to treat osteoarthritis and rheumatoid arthritis. However, many coxibs have been discontinued due to adverse cardiovascular events. COX-2 contains cyclooxygenase (COX) and peroxidase (POX) sites. COX-2 inhibitors block COX activity without affecting POX activity. Recently, quercetin-like flavonoid compounds with OH groups in their B-rings have been found to serve as activators of COX-2 by binding the POX site. Galangin-like flavonol compounds serve as inhibitors of COX-2. Interestingly, nabumetone, flurbiprofen axetil, piketoprofen-amide, and nepafenac are ester prodrugs that inhibit COX-2. The combination of galangin-like flavonol compounds with these prodrug metabolites may lead to the development of novel COX-2 inhibitors. This review focuses on the most compelling evidence regarding the role and mechanism of COX-2 in cardiovascular diseases and demonstrates that quercetin-like compounds exert potential cardioprotective effects by serving as cofactors of COX-2.
Proteolysis-targeting chimeras (PROTACs) technology has garnered significant attention over the last 10 years, representing a burgeoning therapeutic approach with the potential to address pathogenic ...proteins that have historically posed challenges for traditional small-molecule inhibitors. PROTACs exploit the endogenous E3 ubiquitin ligases to facilitate degradation of the proteins of interest (POIs) through the ubiquitin-proteasome system (UPS) in a cyclic catalytic manner. Despite recent endeavors to advance the utilization of PROTACs in clinical settings, the majority of PROTACs fail to progress beyond the preclinical phase of drug development. There are multiple factors impeding the market entry of PROTACs, with the insufficiently precise degradation of favorable POIs standing out as one of the most formidable obstacles. Recently, there has been exploration of new-generation advanced PROTACs, including small-molecule PROTAC prodrugs, biomacromolecule-PROTAC conjugates, and nano-PROTACs, to improve the in vivo efficacy of PROTACs. These improved PROTACs possess the capability to mitigate undesirable physicochemical characteristics inherent in traditional PROTACs, thereby enhancing their targetability and reducing off-target side effects. The new-generation of advanced PROTACs will mark a pivotal turning point in the realm of targeted protein degradation. In this comprehensive review, we have meticulously summarized the state-of-the-art advancements achieved by these cutting-edge PROTACs, elucidated their underlying design principles, deliberated upon the prevailing challenges encountered, and provided an insightful outlook on future prospects within this burgeoning field.
Carbohydrates are important components of foods and essential biomolecules performing various biological functions in living systems. A variety of biological activities besides providing fuel have ...been explored and reported for carbohydrates. Some carbohydrates have been approved for the treatment of various diseases; however, carbohydrate-containing drugs represent only a small portion of all of the drugs on the market. This review summarizes several potential development directions of carbohydrate-containing therapeutics, with the hope of promoting the application of carbohydrates in drug development.
On-demand dissolution of hydrogels has shown much potential in easy and pain-free removal of wound dressings. This work firstly describes a type of carbon dots (CDs) for dissolving Ca-alginate ...hydrogel via site-specific mineralization method. The CDs were characterized by two features, which included presence of primary/secondary amine groups and generation of calcium crystals with Ca.sup.2+. Especially, the amount of primary/secondary amine groups on CDs played key role in determining whether hydrogel could be dissolved. When there were sufficient primary/secondary amine groups, the mineralization occurred on CDs rather than alginates due to the hydrogen bond between primary/secondary amine and carboxyl of alginates. Thereby, this promoted the gel-sol transition through Ca.sup.2+ capture from the hydrogels. Moreover, antibacterial test revealed Ca.sup.2+ capture from cell walls, while in vivo test revealed hypoxia relief due to porous structures of the renewed hydrogels. Overall, CDs with sufficient primary/secondary amine groups could dissolve Ca-alginate hydrogel through site-specific mineralization method, accompanying by additional functions of antibacterial and hypoxia relief.
BRDs proteins that recognise chromatin acetylation regulate gene expression, are epigenetic readers and master transcription coactivators. BRDs proteins are now emerging as targets for new ...therapeutic development. Blocking the function of any of BRDs proteins can be a control agent for diseases, such as cancer. Traditional drugs like enzyme inhibitors and protein-protein inhibitors have many limitations. The therapeutic efficacy of them remains to be proven. Recently, Proteolysis-Targeting Chimaeras (PROTACs) have become an advanced tool in therapeutic intervention as they remove disease-causing proteins. Extremely potent and efficacious small-molecule PROTACs of the BRDs proteins, based on available, potent, and selective BRDs inhibitors, have been reported. This review presents a comprehensive overview of the development of PROTACs for BRDs proteins regulation in cancer, and the chances and challenges associated with this area are also highlighted.
Atherosclerosis, characterized by the formation of fat-laden plaques, is a chronic inflammatory disease. ABCA1 promotes cholesterol efflux, reduces cellular cholesterol accumulation, and regulates ...anti-inflammatory activities in an apoA-I- or ANXA1-dependent manner. The latter activity occurs by mediating the efflux of ANXA1, which plays a critical role in anti-inflammatory effects, cholesterol transport, exosome and microparticle secretion, and apoptotic cell clearance. ApoA-I increases ANXA1 expression via the ERK, p38MAPK, AKT, and PKC pathways. ApoA-I regulates the signaling pathways by binding to ABCA1, suggesting that apoA-I increases ANXA1 expression by binding to ABCA1. Furthermore, ANXA1 may increase ABCA1 expression. ANXA1 increases PPARγ expression by modulating STAT6 phosphorylation. PPARγ also increases ANXA1 expression by binding to the promoter of ANXA1. Therefore, ABCA1, PPARγ, and ANXA1 may form a feedback loop and regulate each other. Interestingly, the ANXA1 needs to be externalized to the cell membrane or secreted into the extracellular fluids to exert its anti-inflammatory properties. ABCA1 transports ANXA1 from the cytoplasm to the cell membrane by regulating lipidization and serine phosphorylation, thereby mediating ANXA1 efflux, likely by promoting microparticle and exosome release. The direct role of ABCA1 expression and ANXA1 release in atherosclerosis has been unclear. In this review, we focus on the role of ANXA1 in atheroprogression and its novel interaction with ABCA1, which may be useful for providing basic knowledge for the development of novel therapeutic targets for atherosclerosis and cardiovascular disease.
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