Targeting Cholesterol Metabolism Research Articles

Gypenoside L inhibits hepatocellular carcinoma by targeting the SREBP2-HMGCS1 axis and enhancing immune response

Hepatocellular carcinoma (HCC) is a malignant tumor that occurs in the liver, with a high degree of malignancy and relatively poor prognosis. Gypenoside L has inhibitory effects on liver cancer cells. However, its mechanism of action is still unclear. This study aims to investigate the inhibitory effects of gypenoside L on HCC in vitro and in vivo, and explore its potential mechanisms. The results showed that gypenoside L reduced the cholesterol and triglyceride content in HepG2 and Huh-7 cells, inhibited cell proliferation, invasion and metastasis, arrested cell cycle at G0/G1 phase, promoted cell apoptosis. Mechanistically, it targeted the transcription factor SREPB2 to inhibit the expression of HMGCS1 protein and inhibited the downstream proteins HMGCR and MVK, thereby regulating the mevalonate (MVA) pathway. Overexpression HMGCS1 led to significant alterations in the cholesterol metabolism pathway of HCC, which mediated HCC cell proliferation and conferred resistance to the therapeutic effect of gypenoside L. In vivo, gypenoside L effectively suppressed HCC growth in tumor-bearing mice by reducing cholesterol production, exhibiting favorable safety profiles and minimal toxic side effects. Gypenoside L modulated cholesterol homeostasis, enhanced expression of inflammatory factors by regulating MHC I pathway-related proteins to augment anticancer immune responses. Clinical samples from HCC patients also exhibited high expression levels of MVA pathway-related genes in tumor tissues. These findings highlight gypenoside L as a promising agent for targeting cholesterol metabolism in HCC while emphasizing the effectiveness of regulating the SREBP2-HMGCS1 axis as a therapeutic strategy.

Metabolic dysregulation in obese women and the carcinogenesis of gynecological tumors: A review.

Obesity is a significant health issue associated with increased cancer risks, including gynecological malignancies. The worldwide rise in obesity rates is significantly impacting both cancer development and treatment outcomes. Adipose tissue plays a crucial role in metabolism, secreting various substances that can influence cancer formation. In obese individuals, dysfunctional adipose tissue can contribute to cancer development through inflammation, insulin resistance, hormonal changes, and abnormal cholesterol metabolism. Studies have shown a strong correlation between obesity and gynecological cancers, particularly endometrial and breast cancers. Obesity not only increases the risk of developing these cancers but is also associated with poorer outcomes. Additionally, obesity affects the perioperative management of gynecological cancers, requiring specialized care due to increased complications and resistance to therapy. Treatment strategies for managing metabolic dysregulation in patients with gynecological cancers include weight management, statin therapy, and insulin-sensitizing medications. Emerging studies suggest that interventions like intermittent fasting and caloric restriction may enhance the effectiveness of cancer treatments. Furthermore, targeting cholesterol metabolism, such as with statins or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, shows potential in cancer therapy. In conclusion, addressing metabolic issues, particularly obesity, is crucial in preventing and treating gynecological malignancies. Personalized approaches focusing on weight management and metabolic reprogramming may improve outcomes in these patients.

CSN6-SPOP-HMGCS1 Axis Promotes Hepatocellular Carcinoma Progression via YAP1 Activation.

Cholesterol metabolism has important roles in maintaining membrane integrity and countering the development of diseases such as obesity and cancers. Cancer cells sustain cholesterol biogenesis for their proliferation and microenvironment reprograming even when sterols are abundant. However, efficacy of targeting cholesterol metabolism for cancer treatment is always compromised. Here it is shown that CSN6 is elevated in HCC and is a positive regulator of hydroxymethylglutaryl-CoA synthase 1 (HMGCS1) of mevalonate (MVA) pathway to promote tumorigenesis. Mechanistically, CSN6 antagonizes speckle-type POZ protein (SPOP) ubiquitin ligase to stabilize HMGCS1, which in turn activates YAP1 to promote tumor growth. In orthotopic liver cancer models, targeting CSN6 and HMGCS1 hinders tumor growth in both normal and high fat diet. Significantly, HMGCS1 depletion improves YAP inhibitor efficacy in patient derived xenograft models. The results identify a CSN6-HMGCS1-YAP1 axis mediating tumor outgrowth in HCC and propose a therapeutic strategy of targeting non-alcoholic fatty liver diseases- associated HCC.

Cholesterol metabolism in tumor microenvironment: cancer hallmarks and therapeutic opportunities.

Cholesterol is crucial for cell survival and growth, and dysregulation of cholesterol homeostasis has been linked to the development of cancer. The tumor microenvironment (TME) facilitates tumor cell survival and growth, and crosstalk between cholesterol metabolism and the TME contributes to tumorigenesis and tumor progression. Targeting cholesterol metabolism has demonstrated significant antitumor effects in preclinical and clinical studies. In this review, we discuss the regulatory mechanisms of cholesterol homeostasis and the impact of its dysregulation on the hallmarks of cancer. We also describe how cholesterol metabolism reprograms the TME across seven specialized microenvironments. Furthermore, we discuss the potential of targeting cholesterol metabolism as a therapeutic strategy for tumors. This approach not only exerts antitumor effects in monotherapy and combination therapy but also mitigates the adverse effects associated with conventional tumor therapy. Finally, we outline the unresolved questions and suggest potential avenues for future investigations on cholesterol metabolism in relation to cancer.

The role of cholesterol metabolism in lung cancer.

Elevated serum cholesterol metabolism is associated with a reduced risk of lung cancer. Disrupted cholesterol metabolism is evident in both lung cancer patients and tumor cells. Inhibiting tumor cell cholesterol uptake or biosynthesis pathways, through the modulation of receptors and enzymes such as liver X receptor and sterol-regulatory element binding protein 2, effectively restrains lung tumor growth. Similarly, promoting cholesterol excretion yields comparable effects. Cholesterol metabolites, including oxysterols and isoprenoids, play a crucial role in regulating cholesterol metabolism within tumor cells, consequently impacting cancer progression. In lung cancer patients, both the cholesterol levels in the tumor microenvironment and within tumor cells significantly influence cell growth, proliferation, and metastasis. The effects of cholesterol metabolism are further mediated by the reprogramming of immune cells such as T cells, B cells, macrophages, myeloid-derived suppressor cells, among others. Ongoing research is investigating drugs targeting cholesterol metabolism for clinical treatments. Statins, targeting the cholesterol biosynthesis pathway, are widely employed in lung cancer treatment, either as standalone agents or in combination with other drugs. Additionally, drugs focusing on cholesterol transportation have shown promise as effective therapies for lung cancer. In this review, we summarized current research regarding the rule of cholesterol metabolism and therapeutic advances in lung cancer.

Cholesterol homeostasis confers glioma malignancy triggered by hnRNPA2B1-dependent regulation of SREBP2 and LDLR.

Dysregulation of cholesterol metabolism is a significant characteristic of glioma, yet the underlying mechanisms are largely unknown. N6-methyladenosine (m6A) modification has been implicated in promoting tumor development and progression. The aim of this study was to determine the key m6A regulatory proteins involved in the progression of glioma, which is potentially associated with the reprogramming of cholesterol homeostasis. Bioinformatics analysis was performed to determine the association of m6A modification with glioma malignancy from The Cancer Genome Atlas and Genotype-Tissue Expression datasets. Glioma stem cell (GSC) self-renewal was determined by tumor sphere formation and bioluminescence image assay. RNA sequencing and lipidomic analysis were performed for cholesterol homeostasis analysis. RNA immunoprecipitation and luciferase reporter assay were performed to determine hnRNPA2B1-dependent regulation of sterol regulatory element-binding protein 2 (SREBP2) and low-density lipoprotein receptor (LDLR) mRNA. The methylation status of hnRNPA2B1 promoter was determined by bioinformatic analysis and methylation-specific PCR assay. Among the m6A-regulatory proteins, hnRNPA2B1 was demonstrated the most important independent prognostic risk factor for glioma. hnRNPA2B1 ablation exhibited a significant tumor-suppressive effect on glioma cell proliferation, GSC self-renewal and tumorigenesis. hnRNPA2B1 triggers de novo cholesterol synthesis by inducing HMGCR through the stabilization of SREBP2 mRNA. m6A modification of SREBP2 or LDLR mRNA is required for hnRNPA2B1-mediated mRNA stability. The hypomethylation of cg21815882 site on hnRNPA2B1 promoter confers elevated expression of hnRNPA2B1 in glioma tissues. The combination of targeting hnRNPA2B1 and cholesterol metabolism exhibited remarkable antitumor effects, suggesting valuable clinical implications for glioma treatment. hnRNPA2B1 facilitates cholesterol uptake and de novo synthesis, thereby contributing to glioma stemness and malignancy.

Cholesterol Metabolism in Pancreatic Cancer.

Pancreatic cancer's substantial impact on cancer-related mortality, responsible for 8% of cancer deaths and ranking fourth in the US, persists despite advancements, with a five-year relative survival rate of only 11%. Forecasts predict a 70% surge in new cases and a 72% increase in global pancreatic cancer-related deaths by 2040. This review explores the intrinsic metabolic reprogramming of pancreatic cancer, focusing on the mevalonate pathway, including cholesterol biosynthesis, transportation, targeting strategies, and clinical studies. The mevalonate pathway, central to cellular metabolism, significantly shapes pancreatic cancer progression. Acetyl coenzyme A (Acetyl-CoA) serves a dual role in fatty acid and cholesterol biosynthesis, fueling acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) development. Enzymes, including acetoacetyl-CoA thiolase, 3-hydroxy-3methylglutaryl-CoA (HMG-CoA) synthase, and HMG-CoA reductase, are key enzymes in pancreatic cancer. Inhibiting HMG-CoA reductase, e.g., by using statins, shows promise in delaying PanIN progression and impeding pancreatic cancer. Dysregulation of cholesterol modification, uptake, and transport significantly impacts tumor progression, with Sterol O-acyltransferase 1 (SOAT1) driving cholesterol ester (CE) accumulation and disrupted low-density lipoprotein receptor (LDLR) expression contributing to cancer recurrence. Apolipoprotein E (ApoE) expression in tumor stroma influences immune suppression. Clinical trials targeting cholesterol metabolism, including statins and SOAT1 inhibitors, exhibit potential anti-tumor effects, and combination therapies enhance efficacy. This review provides insights into cholesterol metabolism's convergence with pancreatic cancer, shedding light on therapeutic avenues and ongoing clinical investigations.

Pre-Clinical Validation of Targeting Cholesterol Metabolism for Radiotherapy Sensitization in Head and Neck Cancer

This study examines the potential benefits of targeting cholesterol metabolism in combination with radiation therapy (RT) for treating Head and Neck Squamous Cell Carcinoma (HNSCC). Despite advancements in RT delivery, 60% of patients still experience a relapse within 2 years, highlighting the need for improved treatment strategies. Our hypothesis is that a specific, biological response to RT by a subset of tumor cells drives radio-resistance and recurrence, and that targeting cholesterol metabolism may be an effective way to improve RT efficacy. To identify radiation-induced biological responses, whole-genome RNA sequencing analysis was carried out on Cal27 (HPV-) and UMSCC47 (HPV+) cell lines after X-Ray (6MeV Linac) or proton (pencil beam scanning, center part of SOBP) radiations. Potential radio-resistance targets were identified by comparing RT-induced transcriptomic changes with publicly available GEO and TCGA transcriptomic data from human HNSCC samples. Cholesterol metabolism as a driver of HNSCC radio-resistance was validated in vitro by pharmacological and genetic approaches. Transcriptomic analysis revealed a significant increase in 11 genes related to sterol and cholesterol in both the Cal27 and UMSCC47 cell lines after radiation exposure (pathway functional enrichment analysis, p = 2.05e-05). High expression of these RT-induced cholesterol gene signatures correlated with decreased overall survival among HNSCC patients based on the TCGA database (log rank p = 0.022, HR = 1.4). Moreover, a Gene Set Enrichment Analysis of the GSE23036 dataset (pre-treatment HNSCC tumors: locoregional recurrence vs. nonrecurrence) also linked cholesterol metabolism and local recurrence (p = 0.002, FDR = 0.07, NES = 1.72). Single-cell RNA sequencing data from the GSE164690 dataset revealed high expression of cholesterol metabolism genes in human HNSCC epithelial and mesenchymal fractions. In vitro studies demonstrated that RT increased the nuclear translocation of the master transcription factors controlling cholesterol gene expression SREBP2 and increased the expression of the SREBP2 target gene SQLE at the protein level. In accordance with this result, RT increased cellular cholesterol content and uptake in human (p = 0.027) and murine (p = 0.015) HNSCC cell lines. Drug or genetic targeting of SREBP2 reduced cellular cholesterol levels in HNSCC cells and increased toxicity when combined with RT in both 2D and 3D cell cultures compared to RT alone. Targeting cholesterol metabolism in combination with RT could be beneficial for treating HNSCC. In vivo validation in immunocompetent mouse models and orthotopic patient-derived xenograft models is ongoing.

Dysregulation of cholesterol metabolism in cancer progression.

Cholesterol homeostasis has been implicated in the regulation of cellular and body metabolism. Hence, deregulated cholesterol homeostasis leads to the development of many diseases such as cardiovascular diseases, and neurodegenerative diseases, among others. Recent studies have unveiled the connection between abnormal cholesterol metabolism and cancer development. Cholesterol homeostasis at the cellular level dynamically circulates between synthesis, influx, efflux, and esterification. Any dysregulation of this dynamic process disrupts cholesterol homeostasis and its derivatives, which potentially contributes to tumor progression. There is also evidence that cancer-related signals, which promote malignant progression, also regulate cholesterol metabolism. Here, we described the relationship between cholesterol metabolism and cancer hallmarks, with particular focus on the molecular mechanisms, and the anticancer drugs that target cholesterol metabolism.

Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity.

The concept of targeting cholesterol metabolism to treat cancer has been widely tested in clinics, but the benefits are modest, calling for a complete understanding of cholesterol metabolism in intratumoral cells. We analyze the cholesterol atlas in the tumor microenvironment and find that intratumoral Tcells have cholesterol deficiency, while immunosuppressive myeloid cells and tumor cells display cholesterol abundance. Low cholesterol levels inhibit Tcell proliferation and cause autophagy-mediated apoptosis, particularly for cytotoxic Tcells. In the tumor microenvironment, oxysterols mediate reciprocal alterations in the LXR and SREBP2 pathways to cause cholesterol deficiency of Tcells, subsequently leading to aberrant metabolic and signaling pathways that drive Tcell exhaustion/dysfunction. LXRβ depletion in chimeric antigen receptor T (CAR-T) cells leads to improved antitumor function against solid tumors. Since Tcell cholesterol metabolism and oxysterols are generally linked to other diseases, the new mechanism and cholesterol-normalization strategy might have potential applications elsewhere.

The role of cholesterol metabolism in tumor therapy, from bench to bed.

Cholesterol and its metabolites have important biological functions. Cholesterol is able to maintain the physical properties of cell membrane, play an important role in cellular signaling, and cellular cholesterol levels reflect the dynamic balance between biosynthesis, uptake, efflux and esterification. Cholesterol metabolism participates in bile acid production and steroid hormone biosynthesis. Increasing evidence suggests a strict link between cholesterol homeostasis and tumors. Cholesterol metabolism in tumor cells is reprogrammed to differ significantly from normal cells, and disturbances of cholesterol balance also induce tumorigenesis and progression. Preclinical and clinical studies have shown that controlling cholesterol metabolism suppresses tumor growth, suggesting that targeting cholesterol metabolism may provide new possibilities for tumor therapy. In this review, we summarized the metabolic pathways of cholesterol in normal and tumor cells and reviewed the pre-clinical and clinical progression of novel tumor therapeutic strategy with the drugs targeting different stages of cholesterol metabolism from bench to bedside.

MiR-33a and Its Association with Lipid Profile in Patients with Carotid Atherosclerosis.

Atherosclerosis is a chronic inflammatory disease with a complex, multifactorial pathogenesis, which includes lipid metabolism alterations. miR-33a is a microRNA that plays a key role in cholesterol efflux and promotes atherosclerosis, yet its relationship with lipid markers in carotid atherosclerosis (CA) remains unclear. The objective is to evaluate possible associations between miR-33a expression and lipid biomarkers in patients with CA. This was a prospective study that included 61 patients (median age 66.0 years, 55.7% male) with evidence of CA. Lipid profile (total cholesterol, triglycerides [TG], high-density lipoprotein [HDL] and low-density lipoprotein [LDL] cholesterol) was analyzed. Extraction and quantification of miR-33a-5p/3p was performed according to protocol. Patients were further divided depending on the target LDL level (<1.8 mmol/L). Patients with CA had relatively favorable LDL levels with a median of 2.0 mmol/L. Both miR-33a-5p and miR-33a-3p levels were lower in patients with less than targeted LDL levels (37.4 and 38.3 vs. 41.8 and 42.5 respectively, p < 0.05). A significant positive correlation between expression levels of miR-33a-5p/3p and degree of carotid stenosis was found (r = 0.44 and r = 0.38 respectively, p < 0.05). In a univariate linear regression model miR-33a-3p/5p was positively associated with LDL cholesterol (p = 0.02). miR-33a up-regulation is associated with CA and may, in fact, be a key player by targeting cholesterol metabolism. A decrease in LDL cholesterol (<1.8 mmol/L) corresponded to lower levels of miR-33a, yet the direction and causality of this association remains unclear.

The roles of ATP-binding cassette transporter A1 and its substrate cholesterol in head and neck cancers.

Head and neck cancer (HNC), which is among the deadliest malignancies, is the seventh most common cancer worldwide. How cholesterol homeostasis is linked to human cancers has long been a source of curiosity. One of the few proteins that are involved in cholesterol homeostasis is ATP-binding cassette transporter A1 (ABCA1), which is broadly expressed in numerous tissues. ABCA1 increases cholesterol efflux, inhibits cholesterol deposition in cells, and modulates anticancer activities. Therefore, it is not surprising that decreased ABCA1 activity and altered cholesterol homeostasis are implicated in the patho-physiology of HNCs. In this review, we focus on the role of cholesterol metabolism in the patho-physiology and progression of HNCs, with an emphasis on biological effects of ABCA1 transporters. We also review therapeutic approaches targeting cholesterol metabolism, as well as how combining such approaches with existing anticancer treatments may have synergistic effects and therefore open up new therapeutic avenues.

A novel polyphyllin I-based liposome delivery system sensitizes hepatic carcinoma to doxorubicin via cholesterol modulation

Cholesterol and its metabolites act as important signaling molecules that promote tumor development. In recent years, increasing evidence has indicated that targeting cholesterol biosynthesis, metabolism, and membrane distribution could potentially sensitize cancer cells to chemotherapy. However, because of the lack of selectivity and the large differences in half-life, metabolism, and clearance between drugs, combining cholesterol inhibitors with chemotherapy agents can produce toxic side effects and contradictory results, making this kind of treatment highly controversial. Here, we developed a PPI-based multifunctional liposome system to effectively cope with the above challenges. As a steroidal saponin, PPI acts as a membrane stabilizer to replace the cholesterol needed to form liposomes, avoiding the shortcomings caused by extra cholesterol intake. Moreover, as a chemotherapy adjuvant, PPI has great potential to interfere with cancer-derived cholesterol disorders, exerting a cholesterol-lowering effect as strong as lovastatin. The expression of important cholesterol synthesis-related proteins, SOAT1, HMGCR, and SREBP2, were only 1/3-1/2 of lovastatin. In addition, by forming complexes with membrane cholesterol, PPI not only improves plasma membrane fluidity and permeability but also disrupt the distribution of lipid rafts, which decreased the expression of ABC transporters to 0.6–1.0-fold, allowing more chemotherapy agents to reach the intracellular targets. Finally, PPI-DOX co-loaded liposomes (DLPs) exhibited stronger tumor inhibition effect in in vivo animal studies, which was 1.3-fold that of Chol-DOX-LP. Therefore, PPI-based liposomes offer a new strategy and opportunity for cancer treatment by combining cancer-derived cholesterol modulation with other anti-cancer therapies.

Roles of ABCA1 in cancer.

Studies have indicated that anticancer drugs targeting cholesterol metabolism have clinical significance. From the perspective of the mechanism of cholesterol excretion from cells, ATP-binding cassette (ABC)A1 has an essential role that cannot be ignored. ABCA1 is located on the cell membrane and able to mediate the efflux of lipids, such as intracellular cholesterol, thereby initiating reverse cholesterol transport to reduce the intracellular cholesterol level. Therefore, inducing the expression of ABCA1 may become a new breakthrough point in cancer therapy.

Blocking cholesterol efflux mechanism is a potential target for antilymphoma therapy.

Cholesterol is an essential plasma membrane lipid for the maintenance of cellular homeostasis and cancer cell proliferation. Free cholesterol is harmful to cells; therefore, excessive free cholesterol must be quickly esterified by acetyl‐coenzyme A:cholesterol acetyltransferase (ACAT) and exported by scavenger receptor class B member I (SR‐BI) or ATP‐binding cassette protein A1 from specific cells such as macrophage foam cells, which contain cholesteryl ester‐derived vacuoles. Many vacuoles are present in the cytoplasm of Burkitt lymphoma cells. In this study, we observed that these vacuoles are often seen in high‐grade lymphomas. Cell culture study using lymphoma cell lines found that esterified cholesterol is the main component of these vacuoles and the expression of cholesterol metabolism‐related molecules was significantly upregulated in lymphoma cell lines, with SR‐BI and ACAT inhibitors (BLT‐1 and CI‐976, respectively) impeding lymphoma cell proliferation. Cytoplasmic free cholesterol was increased by ACAT and SR‐BI inhibitors, and the accumulation of free cholesterol induced lymphoma cell apoptosis by inducing endoplasmic reticulum stress. Furthermore, synergistic effects of SR‐BI and ACAT inhibitors were observed in a preclinical study. Treatment with SR‐BI inhibitor suppressed lymphoma progression in a tumor‐bearing mouse model, whereas ACAT inhibitor did not. Therefore, SR‐BI inhibitors are potential new antilymphoma therapeutics that target cholesterol metabolism.

Targeting Cholesterol Metabolism as Efficient Antiviral Strategy Against the Hepatitis E Virus.

Background and aimsThe Hepatitis E virus hijacks the endosomal system for its release. These structures are highly dependent on cholesterol. Hence, this study investigates the impact of HEV on cholesterol-metabolism, the effect of intracellular cholesterol content on HEV-release and the potential of cholesterol-modulators to serve as antivirals.MethodsIntracellular cholesterol-content of cells was modulated and impacts on HEV were monitored using qPCR, Western blot, microscopy, virus-titration and density-gradient centrifugation. Blood-lipids and HEV-RNA were routinely quantified in chronically infected patients during follow-up visits.ResultsIn HEV-infected cells, decreased levels of cholesterol are found. In patients, HEV infection decreases serum-lipid concentrations. Importantly, statin treatment herein increases viral titers. Similarly, reduction of intracellular cholesterol via simvastatin treatment increases viral release in vitro. On the contrary, elevating intracellular cholesterol via LDL or 25-hydroxycholesterol strongly reduces viral release due to enhanced lysosomal degradation of HEV. Drug-induced elevation of intracellular cholesterol via fenofibrate or PSC833 impairs HEV release via the same mechanism.ConclusionsThis study analyses the crosstalk between HEV and intracellular cholesterol. The results highlight the importance of an intact cholesterol homeostasis for HEV-release and thereby identify a potential target for antiviral strategies. Especially fenofibrate is considered a promising novel antiviral against HEV. Beyond this, the study may help clinicians evaluating co-treatments of HEV-infected patients with statins, as this may be counter indicated.

Cholesterol metabolism: At the cross road between cancer cells and immune environment.

Mevalonate pathway is a highly conserved pathway that produces isoprenoids and cholesterol, and it is often increased in cancer cells. Cholesterol, upstream metabolites including isoprenoids and cholesterol derivatives such as oxysterols modulate cell proliferation, motility, stemness and drug resistance. Moreover, when produced by cancer cells or immune infiltrating cells, they modulate the activity of immune populations of the tumor microenvironment. In this review, we will focus on the recent findings demonstrating that cholesterol derivatives may regulate tumor immune recognition or immune escape, playing a critical role in the immune surveillance. Since the mevalonate pathway is druggable, a deeper knowledge of the metabolic cross talks existing between the mevalonate pathway of cancer cells and immune cells may help to identify novel agents targeting cholesterol metabolism, able to boost the anti-tumor activity of the immune populations.

Cholesterol and 27-hydroxycholesterol promote thyroid carcinoma aggressiveness

Cholesterol mediates its proliferative and metastatic effects via the metabolite 27-hydroxycholesterol (27-HC), at least in breast and endometrial cancer. We determined the serum lipoprotein profile, intratumoral cholesterol and 27-HC levels in a cohort of patients with well-differentiated papillary thyroid carcinoma (PTC; low/intermediate and high risk), advanced thyroid cancers (poorly differentiated, PDTC and anaplastic thyroid carcinoma, ATC) and benign thyroid tumors, as well as the expression of genes involved in cholesterol metabolism. We investigated the gene expression profile, cellular proliferation, and migration in Nthy-ori 3.1 and CAL-62 cell lines loaded with human low-density lipoprotein (LDL). Patients with more aggressive tumors (high-risk PTC and PDTC/ATC) showed a decrease in blood LDL cholesterol and apolipoprotein B. These changes were associated with an increase in the expression of the thyroid’s LDL receptor, whereas 3-hydroxy-3-methylglutaryl-CoA reductase and 25-hydroxycholesterol 7-alpha-hydroxylase were downregulated, with an intratumoral increase of the 27-HC metabolite. Furthermore, LDL promoted proliferation in both the Nthy-ori 3.1 and CAL-62 thyroid cellular models, but only in ATC cells was its cellular migration increased significantly. We conclude that cholesterol and intratumoral accumulation of 27-HC promote the aggressive behavior process of PTC. Targeting cholesterol metabolism could be a new therapeutic strategy in thyroid tumors with poor prognosis.

Cholesterol Metabolism: A Potential Therapeutic Target in Glioblastoma.

Glioblastoma is a highly lethal adult brain tumor with no effective treatments. In this review, we discuss the potential to target cholesterol metabolism as a new strategy for treating glioblastomas. Twenty percent of cholesterol in the body is in the brain, yet the brain is unique among organs in that it has no access to dietary cholesterol and must synthesize it de novo. This suggests that therapies targeting cholesterol synthesis in brain tumors might render their effects without compromising cell viability in other organs. We will describe cholesterol synthesis and homeostatic feedback pathways in normal brain and brain tumors, as well as various strategies for targeting these pathways for therapeutic intervention.