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Cholesterol is a lipid molecule that plays an essential role in a number of biological processes, both physiological and pathological. It is an essential structural constituent of cell membranes, and it is fundamental for biosynthesis, integrity, and functions of biological membranes, including membrane trafficking and signaling. Moreover, choleste...
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... In this context, reduced cholesterol biosynthesis can impair the production and secretion of Shh, as well as its interaction with PTCH1 and SMO (Blassberg and Jacob, 2017). Additionally, decreased cholesterol availability can alter the membrane fluidity and organization of lipid rafts, which are microdomains enriched in cholesterol and sphingolipids that facilitate the assembly and function of Shh signaling components (Mann and Beachy, 2004;Petrova et al., 2013;Vona et al., 2021). Moreover, lowered cholesterol intake can modulate the expression and activity of the Hh acetyltransferase (Hhat) enzyme, an enzyme that catalyzes the palmitoylation of Shh and regulates its stability and potency (Tuladhar et al., 2019). ...
... For example, methyl-bcyclodextrin can deplete cholesterol and reduce CD44 aggregation on lipid rafts, thereby enhancing CD44 binding to HA on T cells. In addition, high levels of cholesterol can promote the entry of CD44 into lipid rafts, resulting in decreased binding between CD44 and Ezrin and subsequently inhibiting the migration and invasion of tumor cells (36). ...
CD44 is a ubiquitous leukocyte adhesion molecule involved in cell-cell interaction, cell adhesion, migration, homing and differentiation. CD44 can mediate the interaction between leukemic stem cells and the surrounding extracellular matrix, thereby inducing a cascade of signaling pathways to regulate their various behaviors. In this review, we focus on the impact of CD44s/CD44v as biomarkers in leukemia development and discuss the current research and prospects for CD44-related interventions in clinical application.
... Cholesterol is an essential lipid molecule involved in both physiological and pathological processes within the human body. [1] It serves as a crucial component of cell membrane, contributing to cell integrity and trafficking functions. [1] Additionally, cholesterol is a precursor in several biosynthesis pathways, including those for vitamin D, oxysterols, cholesteryl ester, and bile acid. ...
... [1] It serves as a crucial component of cell membrane, contributing to cell integrity and trafficking functions. [1] Additionally, cholesterol is a precursor in several biosynthesis pathways, including those for vitamin D, oxysterols, cholesteryl ester, and bile acid. [1] Clinical studies have highlighted a correlation between cholesterol and the incidence of atherosclerosis. ...
... [1] Additionally, cholesterol is a precursor in several biosynthesis pathways, including those for vitamin D, oxysterols, cholesteryl ester, and bile acid. [1] Clinical studies have highlighted a correlation between cholesterol and the incidence of atherosclerosis. [2] Cholesterol levels are important biomarkers for monitoring health conditions. ...
Cholesterol is an essential lipid molecule associated with various physiological and pathological processes in the human body. Elevated cholesterol levels are correlated with several diseases, such as atherosclerosis, making cholesterol a critical biomarker for health monitoring. Molecular imprinting technology was selected to fabricate cholesterol imprinted microsphere (CHOL‐IP). This approach creates tailor‐made binding sites within polymer matrices for capturing cholesterol. However, the limited functional group in steroid derivative pose a challenge for the imprinting strategy. In this study, we successfully synthesized CHOL‐IP using a metal chelating monomer, N,N′‐vinylbenzyl iminodiacetic acid (VBIDA), in conjunction with copper (II) ions. The metal coordination approach facilitated strong binding forces, resulting in improved stability and specificity of the molecularly imprinted polymer (MIP). The synthesized CHOL‐IP was tested with pooled human serum samples containing cholesterol, HDL, and LDL. The CHOL‐IP exhibited significantly higher binding efficiency towards these compounds compared to the control polymer (CP). The application of a metal‐chelating functional monomer in the synthesized CHOL‐IP revealed the potential for enhancing its strong binding property toward cholesterol. This suggests that CHOL‐IP could be employed in the development of a cholesterol‐imprinted biosensor, providing an alternative tool for cholesterol analysis in medical detection applications.
... Cholesterol plays a fundamental and multifaceted role in the structure and function of lipid rafts affecting structural integrity [21], modulating fluidity, organization and segregation of lipids and proteins within lipid rafts, modulation of cellular signaling pathways, endocytosis, and intracellular trafficking while cholesterol rich lipid rafts are often targeted by pathogens for cellular entry [21,22,[32][33][34][35]. Oxysterols, derivatives of cholesterol that can either promote or inhibit the formation of lipid rafts, play a crucial role in signaling processes [36,37]. ...
The purpose of this review is to succinctly examine the methodologies used in lipid raft research in the brain and to highlight the drawbacks of some investigative approaches. Lipid rafts are biochemically and biophysically different from the bulk membrane. A specific lipid environment within membrane domains provides a harbor for distinct raftophilic proteins, all of which in concert create a specialized platform orchestrating various cellular processes. Studying lipid rafts has proved to be arduous due to their elusive nature, mobility, and constant dynamic reorganization to meet the cellular needs. Studying neuronal lipid rafts is particularly cumbersome due to the immensely complex regional molecular architecture of the central nervous system. Biochemical fractionation, performed with or without detergents, is still the most widely used method to isolate lipid rafts. However, the differences in solubilization when various detergents are used has exposed a dire need to find more reliable methods to study particular rafts. Biochemical methods need to be complemented with other approaches such as live-cell microscopy, imaging mass spectrometry, and the development of specific non-invasive fluorescent probes to obtain a more complete image of raft dynamics and to study the spatio-temporal expression of rafts in live cells.
... Recent evidence suggests that cancer cells contain more lipid rafts than their nontumorigenic counterparts and that the disruption of their integrity is associated with the activation of many signaling processes involved in cancer development and progression [22,23]. ...
Cholesterol (CHOL) is a multifaceted lipid molecule. It is an essential structural component of cell membranes, where it cooperates in regulating the intracellular trafficking and signaling pathways. Additionally, it serves as a precursor for vital biomolecules, including steroid hormones, isoprenoids, vitamin D, and bile acids. Although CHOL is normally uptaken from the bloodstream, cells can synthesize it de novo in response to an increased requirement due to physiological tissue remodeling or abnormal proliferation, such as in cancer. Cumulating evidence indicated that increased CHOL biosynthesis is a common feature of breast cancer and is associated with the neoplastic transformation of normal mammary epithelial cells. After an overview of the multiple biological activities of CHOL and its derivatives, this review will address the impact of de novo CHOL production on the promotion of breast cancer with a focus on mammary stem cells. The review will also discuss the effect of de novo CHOL production on in situ and invasive carcinoma and its impact on the response to adjuvant treatment. Finally, the review will discuss the present and future therapeutic strategies to normalize CHOL biosynthesis.
... These cholesterol-rich regions are characterized by their higher lipid order and serve as platforms for various physiological processes, such as cell signaling. However, an irregular upsurge in cholesterol levels within lipid rafts can disrupt normal cellular signaling, initiating various pathological states, including cancer and CVDs (28). Moreover, cholesterol is critical for the proper membrane receptor function, including receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs), which are essential for cell signaling (29). ...
Colorectal cancer (CRC) is one of the most lethal human malignancies, and with the growth of societies and lifestyle changes, the rate of people suffering from it increases yearly. Important factors such as genetics, family history, nutrition, lifestyle, smoking, and alcohol can play a significant role in increasing susceptibility to this cancer. On the other hand, the metabolism of several macromolecules is also involved in the fate of tumors and immune cells. The evidence discloses that cholesterol and its metabolism can play a role in the pathogenesis of several cancers because there appears to be an association between cholesterol levels and CRC, and cholesterol-lowering drugs may reduce the risk. Furthermore, changes or mutations of some involved genes in cholesterol metabolism, such as CYP7A1 as well as signaling pathways, such as mitogen-activated protein kinase (MAPK), can play a role in CRC pathogenesis. This review summarized and discussed the role of cholesterol in the pathogenesis of CRC as well as available cholesterol-related therapeutic approaches in CRC.
... Cholesterol and lipid rafts have been considered important therapeutic targets in various diseases (Sviridov et al., 2020;Vona et al., 2021). Examining the involvement of primary cilia provides novel insights into the therapeutic approaches targeting cholesterol and lipid rafts. ...
... and hepatocellular carcinoma [44] where EZH2i resulted in altered cholesterol synthesis. Dysregulation of cholesterol homeostasis can induce cell cycle arrest and apoptosis through the activation of specific transcription factors [45]. These results suggest a possible combination with HMG-CoA reductase inhibitors (Statins), currently in use for reduction of elevated cholesterol, may also be clinically relevant for RMS. ...
Background
Rhabdomyosarcomas (RMS) are predominantly paediatric sarcomas thought to originate from muscle precursor cells due to impaired myogenic differentiation. Despite intensive treatment, 5-year survival for patients with advanced disease remains low (< 30%), highlighting a need for novel therapies to improve outcomes. Differentiation therapeutics are agents that induce differentiation of cancer cells from malignant to benign. The histone methyltransferase, Enhancer of Zeste Homolog 2 (EZH2) suppresses normal skeletal muscle differentiation and is highly expressed in RMS tumours.
Results
We demonstrate combining inhibition of the epigenetic modulator EZH2 with the differentiating agent retinoic acid (RA) is more effective at reducing cell proliferation in RMS cell lines than single agents alone. In PAX3-FOXO1 positive RMS cells this is due to an RA-driven induction of the interferon pathway resulting in apoptosis. In fusion negative RMS, combination therapy led to an EZH2i-driven upregulation of myogenic signalling resulting in differentiation. In both subtypes, EZH2 is significantly associated with enrichment of trimethylated lysine 27 on histone 3 (H3K27me3) in genes that are downregulated in untreated RMS cells and upregulated with EZH2 inhibitor treatment. These results provide insight into the mechanism that drives the anti-cancer effect of the EZH2/RA single agent and combination treatment and indicate that the reduction of EZH2 activity combined with the induction of RA signalling represents a potential novel therapeutic strategy to treat both subtypes of RMS.
Conclusions
The results of this study demonstrate the potential utility of combining EZH2 inhibitors with differentiation agents for the treatment of paediatric rhabdomyosarcomas. As EZH2 inhibitors are currently undergoing clinical trials for adult and paediatric solid tumours and retinoic acid differentiation agents are already in clinical use this presents a readily translatable potential therapeutic strategy. Moreover, as inhibition of EZH2 in the poor prognosis FPRMS subtype results in an inflammatory response, it is conceivable that this strategy may also synergise with immunotherapies for a more effective treatment in these patients.
... This observation is consistent with results published by Zheng et al. (2020). The role played by cholesterol in cancer development is widely described but still controversial in the literature (Li et al., 2016;Kuzu et al., 2016;Silvente-Poirot and Poirot, 2012;Vona et al., 2021;Zhang et al., 2021). ...
... Cholesterol's role in lipid rafts and caveolae in the plasma membrane may impact cancer cell proliferation and survival via effects on signaling by receptors such as HER2 [29], EGFR [30] and CXCR4 [31], as well as transducers and effectors such as PI3K [32], SRC family kinases [25] and NOX [33], along with other regulators [34]. However, maintaining cholesterol at normal levels in other cellular membranes and subdomains impacts a wide range of pathways important to cancer cell growth, proliferation and resistance. ...
Statins, a class of HMG-CoA reductase inhibitors best known for their cholesterol-reducing and cardiovascular protective activity, have also demonstrated promise in cancer prevention and treatment. This review focuses on their potential applications in head and neck cancer (HNC), a common malignancy for which established treatment often fails despite incurring debilitating adverse effects. Preclinical and clinical studies have suggested that statins may enhance HNC sensitivity to radiation and other conventional therapies while protecting normal tissue, but the underlying mechanisms remain poorly defined, likely involving both cholesterol-dependent and -independent effects on diverse cancer-related pathways. This review brings together recent discoveries concerning the anticancer activity of statins relevant to HNC, highlighting their anti-inflammatory activity and impacts on DNA-damage response. We also explore molecular targets and mechanisms and discuss the potential to integrate statins into conventional HNC treatment regimens to improve patient outcomes.
