👤 A. Russo

Carnitine O-acetyltransferase (CRAT) is a key mitochondrial enzyme involved in maintaining metabolic homeostasis by mediating the reversible transfer of acetyl groups between acetyl-CoA and carnitine. This enzymatic activity ensures the optimal functioning of mitochondrial carbon flux by preventing acetyl-CoA accumulation, buffering metabolic flexibility, and regulating the balance between fatty acid and glucose oxidation. CRAT’s interplay with the mitochondrial carnitine shuttle, involving carnitine palmitoyltransferases (CPT1 and CPT2) and the carnitine carrier (SLC25A20), underscores its critical role in energy metabolism. Emerging evidence highlights the structural and functional diversity of CRAT and structurally related acetyltransferases across cellular compartments, illustrating their coordinated role in lipid metabolism, amino acid catabolism, and mitochondrial bioenergetics. Moreover, the structural insights into CRAT have paved the way for understanding its regulation and identifying potential modulators with therapeutic applications for diseases such as diabetes, mitochondrial disorders, and cancer. This review examines CRAT’s structural and functional aspects, its relationships with carnitine shuttle members and other carnitine acyltransferases, and its broader role in metabolic health and disease. The potential for targeting CRAT and its associated pathways offers promising avenues for therapeutic interventions aimed at restoring metabolic equilibrium and addressing metabolic dysfunction in disease states. Show less

Lung cancer is a common malignant tumor that occurs in the human body and poses a serious threat to human health and quality of life. The existing treatment methods mainly include surgical treatment, chemotherapy, and radiotherapy. However, due to the strong metastatic characteristics of lung cancer and the emergence of related drug resistance and radiation resistance, the overall survival rate of lung cancer patients is not ideal. There is an urgent need to develop new treatment strategies or new effective drugs to treat lung cancer. Ferroptosis, a novel type of programmed cell death, is different from the traditional cell death pathways such as apoptosis, necrosis, pyroptosis and so on. It is caused by the increase of iron-dependent reactive oxygen species due to intracellular iron overload, which leads to the accumulation of lipid peroxides, thus inducing cell membrane oxidative damage, affecting the normal life process of cells, and finally promoting the process of ferroptosis. The regulation of ferroptosis is closely related to the normal physiological process of cells, and it involves iron metabolism, lipid metabolism, and the balance between oxygen-free radical reaction and lipid peroxidation. A large number of studies have confirmed that ferroptosis is a result of the combined action of the cellular oxidation/antioxidant system and cell membrane damage/repair, which has great potential application in tumor therapy. Therefore, this review aims to explore potential therapeutic targets for ferroptosis in lung cancer by clarifying the regulatory pathway of ferroptosis. Based on the study of ferroptosis, the regulation mechanism of ferroptosis in lung cancer was understood and the existing chemical drugs and natural compounds targeting ferroptosis in lung cancer were summarized, with the aim of providing new ideas for the treatment of lung cancer. In addition, it also provides the basis for the discovery and clinical application of chemical drugs and natural compounds targeting ferroptosis to effectively treat lung cancer. Show less

Background Chemotherapy, radiotherapy, targeted therapy and immunotherapy have demonstrated expected clinical efficacy, while drug resistance remains the predominant limiting factor to therapeutic failure in patients with colorectal cancer (CRC). Although there have been numerous basic and clinical studies on CRC resistance in recent years, few publications utilized the bibliometric method to evaluate this field. The objective of current study was to provide a comprehensive analysis of the current state and changing trends of drug resistance in CRC over the past 20 years. Methods The Web of Science Core Collection (WOSCC) was utilized to extracted all studies regarding drug resistance in CRC during 2002-2021. CiteSpace and online platform of bibliometrics were used to evaluate the contributions of various countries/regions, institutions, authors and journals in this field. Moreover, the recent research hotspots and promising future trends were identified through keywords analysis by CiteSpace and VOSviewer. Results 1451 related publications from 2002 to 2021 in total were identified and collected. The number of global publications in this field has increased annually. China and the USA occupied the top two places with respect to the number of publications, contributing more than 60% of global publications. Sun Yat-sen University and Oncotarget were the institution and journal which published the most papers, respectively. Bardelli A from Italy was the most prolific writer and had the highest H-index. Keywords burst analysis identified that “Growth factor receptor”, “induced apoptosis” and “panitumumab” were the ones with higher burst strength in the early stage of this field. Analysis of keyword emergence time showed that “oxaliplatin resistance”, “MicroRNA” and “epithelial mesenchymal transition (EMT)” were the keywords with later average appearing year (AAY). Conclusions The number of publications and research interest on drug resistance in CRC have been increasing annually. The USA and China were the main driver and professor Bardelli A was the most outstanding researcher in this field. Previous studies have mainly concentrated on growth factor receptor and induced apoptosis. Oxaliplatin resistance, microRNA and EMT as recently appeared frontiers of research that should be closely tracked in the future. Show less

Oxaliplatin is a platinum analog that can interfere with DNA replication and transcription. Continuous exposure to oxaliplatin results in chemoresistance; however, this mechanism is not well known. In this study, oxaliplatin-resistant (OR) colorectal cancer (CRC) cells of HCT116, HT29, SW480 and SW620 were established by gradually increasing the drug concentration to 2.5 μM. The inhibitory concentrations of cell growth by 50% (IC 50 ) of oxaliplatin were 4.40–12.7-fold significantly higher in OR CRC cells as compared to their respective parental (PT) CRC cells. Phospho-Akt and phospho-mammalian target of rapamycin (mTOR) decreased in PT CRC cells but was overexpressed in OR CRC cells in response to oxaliplatin. In addition, an oxaliplatin-mediated decrease in phospho-AMP-activated protein kinase (AMPK) in PT CRC cells induced autophagy. Contrastingly, an increased phospho-AMPK in OR CRC cells was accompanied by a decrease in LC3B, further inducing the activity of glycolytic enzymes, such as glucose transporter 1 (GLUT1), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and phosphofructokinase 1 (PFK1), to mediate cell survival. Inhibition of AMPK in OR CRC cells induced autophagy through inactivation of Akt/mTOR pathway and a decrease in GLUT1, PFKFB3, and PFK1. Collectively, targeting AMPK may provide solutions to overcome chemoresistance in OR CRC cells and restore chemosensitivity to anticancer drugs. Show less

Cytosolic ribosomes (cytoribosomes) are macromolecular ribonucleoprotein complexes that are assembled from ribosomal RNA and ribosomal proteins, which are essential for protein biosynthesis. Mitochondrial ribosomes (mitoribosomes) perform translation of the proteins essential for the oxidative phosphorylation system. The biogenesis of cytoribosomes and mitoribosomes includes ribosomal RNA processing, modification and binding to ribosomal proteins and is assisted by numerous biogenesis factors. This is a major energy-consuming process in the cell and, therefore, is highly coordinated and sensitive to several cellular stressors. In mitochondria, the regulation of mitoribosome biogenesis is essential for cellular respiration, a process linked to cell growth and proliferation. This review briefly overviews the key stages of cytosolic and mitochondrial ribosome biogenesis; summarizes the main steps of ribosome biogenesis alterations occurring during tumorigenesis, highlighting the changes in the expression level of cytosolic ribosomal proteins (CRPs) and mitochondrial ribosomal proteins (MRPs) in different types of tumors; focuses on the currently available information regarding the extra-ribosomal functions of CRPs and MRPs correlated to cancer; and discusses the role of CRPs and MRPs as biomarkers and/or molecular targets in cancer treatment. Show less

AbstractIn the effort to overcome issues of toxicity and resistance inherent to treatment by the approved platinum anticancer agents, a large number of cisplatin variants continues today to be prepared and tested. One of the applied strategies is to use monofunctional platinum complexes that, unlike traditional bifunctional compounds, are able to form only a single covalent bond with nuclear DNA. Chirality, aquation reaction, interaction with guanine and N‐acetyl methionine as well as, intercalation into, binding to and distortion of DNA have been investigated by using both quantum mechanical DFT and molecular dynamics computations aiming at contributing to the elucidation of the molecular mechanism underlying the significantly enhanced spectrum of activity of the monofunctional PtII drug phenanthriplatin. Analogous calculations have been performed in parallel for other two less potent monofunctional PtII drugs, pyriplatin and enpyriplatin, which show very different cytotoxic effects. Show less

The nucleolus is the site of ribosome biogenesis, a complex process that requires the coordinate activity of all three RNA polymerases and hundreds of non-ribosomal factors that participate in the maturation of ribosomal RNA (rRNA) and assembly of small and large subunits. Nevertheless, emerging studies have highlighted the fundamental role of the nucleolus in sensing a variety of cellular stress stimuli that target ribosome biogenesis. This condition is known as nucleolar stress and triggers several response pathways to maintain cell homeostasis, either p53-dependent or p53-independent. The mouse double minute (MDM2)-p53 stress signaling pathways are activated by multiple signals and are among the most important regulators of cellular homeostasis. In this review, we will focus on the role of ribosomal proteins in p53-dependent and p53-independent response to nucleolar stress considering novel identified regulators of these pathways. We describe, in particular, the role of ribosomal protein uL3 (rpL3) in p53-independent nucleolar stress signaling pathways. Show less

Many chemotherapeutic drugs cause nucleolar stress and p53-independent pathways mediating the nucleolar stress response are emerging. Here, we demonstrate that ribosomal stress induced by Actinomycin D (Act D) is associated to the up-regulation of ribosomal protein L3 (rpL3) and its accumulation as ribosome-free form in lung and colon cancer cell lines devoid of p53. Free rpL3 regulates p21 expression at transcriptional and post-translational levels through a molecular mechanism involving extracellular-signal-regulated kinases1/2 (ERK1/2) and mouse double minute-2 homolog (MDM2). Our data reveal that rpL3 participates to cell response acting as a critical regulator of apoptosis and cell migration. It is noteworthy that silencing of rpL3 abolishes the cytotoxic effects of Act D suggesting that the loss of rpL3 makes chemotherapy drugs ineffective while rpL3 overexpression associates to a strong increase of Act D-mediated inhibition of cell migration. Taking together our results show that the efficacy of Act D chemotherapy depends on rpL3 status revealing new specific targets involved in the molecular pathways activated by Act D in cancers lacking of p53. Hence, the development of treatments aimed at upregulating rpL3 may be beneficial for the treatment of these cancers. Show less

Recent evidence showed that a variety of DNA damaging agents including 5-FU and L-OHP impairs ribosomal biogenesis activating a ribosomal stress pathway. Here, we demonstrate that in lung and colon cancer cell lines devoid of p53, the efficacy of 5-FU and L-OHP chemotherapy depends on rpL3 status. Specifically, we demonstrate that ribosomal stress induced by 5-FU and L-OHP is associated to up-regulation of rpL3 and its accumulation as ribosome-free form. We show that rpL3 participates in the cell response to chemotherapy acting as a critical regulator of cell cycle, apoptosis and DNA repair, by modulating p21 expression. Moreover, we demonstrate that rpL3 is able to control DNA repair also independently from p21 status of cell. It is noteworthy that silencing of rpL3 abolishes the cytotoxic effects of 5-FU and L-OH indicating that the loss of rpL3 makes chemotherapy drugs ineffective. Taking together our results shed light on 5-FU and L-OHP mechanism of action and contribute to more effective clinical use of these drugs in cancer therapy. Show less

The hydrolysis of oxaliplatin, a third generation anticancer drug, is expected to play an important role in the activation of this compound before it reaches DNA. The first and second hydrolysis corresponding to the addition of the first water molecule concomitant with the ring-opening, followed by addition of a second water and loss of the monodentate oxalato ligand, respectively, were studied combining density functional theory (DFT) with the conductor-like dielectric continuum model (CPCM) approach. The reaction was studied in neutral and acidic conditions, and all stationary points have been identified. The computed potential energy surfaces show that, for the neutral hydrolysis, the ring-opening reaction is the rate-limiting process, with an activation barrier of about 28 kcal/mol. For the acid degradation in water, according to experimental data, the reaction is expected to proceed in a faster biphasic process, and the rate-limiting process is the ligand detachment that occurs with a barriers of about 22 kcal/mol. According to the calculated results, we expect that the reaction is favored in acidic conditions and that the monoaquated complex should be the species reacting with DNA. Show less