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FC, CE and CLA content in media utilised for experimental purposes (nanomoles per milliliter) 10% Serum in culture media FC CE total CE/FC CLA in CE
Source publication
Tumour are characterised by a high content of cholesteryl esters (CEs) stored in lipid droplets purported to be due to a high rate of intracellular esterification of cholesterol. To verify whether and which pathways involved in CE accumulation are essential in tumour proliferation, the effect of CE deprivation, from both exogenous and endogenous so...
Contexts in source publication
Context 1
... content of culture media Table 1 shows the content in free cholesterol (FC), CE and CLA-CE in culture media with different sera and treatments utilised for experiments. ...
Context 2
... results were confirmed by lipid droplet evaluation (Fig. 3, panel e, f). As expected cholesteryl CLA was detected in FCS and BCS (see Table 1). Accordingly, a substantial increase of cholesteryl CLA in cells cultured with BCS in the presence of Sandoz is strongly suggestive of an exogenous uptake of CE ( Table 2). ...
Citations
... In other studies, culturing cells in delipidated serum inhibited cell proliferation, which was reversed by addition of cholesterol [40,41]. The chemically defined lipid concentrate used in this study contains eight fatty acids (arachidonic acid, linoleic acid, linolenic acid, myristic acid, oleic acid, palmitic acid, palmitoleic acid, and stearic acid) but also contains cholesterol (0.57 mmol/L). ...
Many cancers rely on glucose as an energy source, but it is becoming increasingly apparent that some use alternate substrates to fuel their proliferation. Chronic lymphocytic leukaemia (CLL) is one such cancer. Using flow cytometry and confocal microscopy, low levels of glucose uptake were observed in the OSU-CLL and HG3 CLL cell lines, relative to highly glucose-avid Raji cells (Burkitt's lymphoma). Glucose uptake in CLL cells correlated with low expression of the GLUT1 and GLUT3 receptors. In contrast, both CLL cell lines and primary CLL cells, but not healthy B-cells, were found to rapidly internalise medium- and long-chain, but not short-chain, fatty acids (FAs). Differential FA uptake was also observed in primary cells taken from patients with unmutated immunoglobulin heavy variable chain usage (IGHV) compared to patients with mutated IGHV. Delipidation of the serum in the culture medium slowed the proliferation and significantly reduced the viability of OSU-CLL and HG3 cells; effects that were partially reversed by supplementation with a chemically defined lipid concentrate. These observations highlight the potential importance of fatty acids in the pathogenesis of CLL and raise the possibility that targeting fatty acid utilisation may represent a novel therapeutic and prognostic approach in this disease.
... Reports on the effect of SR-B1/HDL on cancer cell growth are controversial. An in vitro study showed that the growth of tumor cells was directly related to an increase in HDL (54). It has been reported that HDL increased cell proliferation in ER -BCC (42), although, another study found no effect on the proliferation of ER -, PR -, HER -(MDA-MB -231) BCC (55) and another showed a reduction in the number of viable cells (56). ...
Objectives:
High-density lipoprotein (HDL) is necessary for proliferation of several cells. The growth of many kinds of cells, such as breast cancer cells (BCC) is motivated by HDL. Cellular uptake of cholesterol from HDL which increases cell growth is facilitated by scavenger receptors of the B class (SR-BI). The proliferative effect of HDL might be mediated by this receptor. It is also believed that HDL has an anti-apoptotic effect on various cell types and promotes cell growth. This study was designed to investigate SR-BI expression, proliferation and apoptotic effect of HDL on human BCC lines, MCF-7 and MDA-MB-468.
Materials and methods:
Real-time-PCR method was used to evaluate expression of SR-BI, and cholesterol concentration was measured using a cholesterol assay kits (Pars AZ moon, Karaj, Iran). Cell viability was assessed using the MTT test. To identify cell apoptosis, the annexin V-FITC staining test and caspase-9 activity assay were applied.
Results:
Treatment of both cell lines (MCF-7, MDA-MB-468) with HDL results in augmentation of SR-BI mRNA expression and also elevation of the intracellular cholesterol (P<0.01). HDL induced cell proliferation, cell cycle progression, and prevented activation of caspase-9 (P<0.05). We also demonstrated that inhibition of SR-B1 by BLT-1 could reduce cell proliferation, and induction of SR-B1 receptor by quercetin increased HDL-induced proliferation in both cell lines (P<0.05).
Conclusion:
It can be concluded that alteration in HDL levels by SR-B1 activator (Quercetin) or inhibitor (BLT-1) may affect BCC growth and apoptosis induction.
... Apart from poor nutritional status frequently seen in CRC (20), which could be one of the reasons for decreased cho-lesterol synthesis in the liver, it has been recently proposed that reprogramming of lipid metabolism could be responsible for the observed decrease in serum lipid status markers in various types of cancer (20,21). Namely, it has been demonstrated that cancer cells extensively accumulate and use cholesterol (22,23), while such increased needs are satisfied by either upregulated endogenous synthesis (24), or enhanced uptake of circulating cholesterol (25,26). Such rearrangement of cholesterol synthesis and cellular accumulation could have important consequences regarding vitamin D status. ...
Background
Vitamin D deficiency is repeatedly reported in colorectal cancer (CRC). Since cholesterol and vitamin D share common precursor 7-dehydrocholesterol (7-DHC), it would be important to explore the associations of key vitamin D metabolites and serum lipid parameters in patients with high and low grade CRC. The aim of this study was to analyze relationships between serum 25(OH)D3, 24,25(OH)2D3 and 7-DHC levels and serum lipids in patients with CRC, and to evaluate their potential for prediction of risk for development of high grade CRC.
Methods
We recruited 82 patients CRC and 77 controls. 7-DHC, 25(OH)D3 and 24,25(OH)2D3 were quantified by LC-MS/MS methods.
Results
7-DHC, 25(OH)D3 and vitamin D metabolic ratio (VDMR) were significantly lower in CRC patients than in control group (P<0.001, P<0.010, P<0.050 and P<0.050, respectively). 25(OH)D3 levels were higher in patients with grade I CRC when compared to grade II (P<0.050). All vitamin D metabolites positively correlated with total cholesterol (TC) concentration in CRC patients. 25(OH)D3 was significant predictor of increased CRC risk (P<0.010). After adjustment for TC concentration, 25(OH)D3 lost its predictive abilities. However, 25(OH)D3 remained significant predictor of poorly differentiated type of cancer (P<0.050).
Conclusions
We found significant positive association between vitamin D status and serum total cholesterol. Although low 25(OH)D3 was found to be a significant risk factor for CRC development, the obtained results primarily suggest profound impact of cholesterol level on vitamin D status in CRC. However, our results suggest that low 25(OH)D3 might independently contribute to development of poorly differentiated tumor.
... 64 It has been previously indicated that in cell culture studies, the growth of breast cancer cells would occur as a result of HDL addition. 63 Several studies have shown a high expression of the SR-B1 receptor in breast cancer cells that recruit HDL to remove excess cholesterol and enhance required intracellular cholesterol. 42 Enhanced intracellular cholesterol is directly related to an increase in carcinogenesis risk. ...
Breast cancer is a major cause of death globally, and particularly in developed countries. Breast cancer is influenced by cholesterol membrane content, by affecting the signaling pathways modulating cell growth, adherence, and migration. Furthermore, steroid hormones are derived from cholesterol and these play a key role in the pathogenesis of breast cancer. Although most findings have reported an inverse association between serum high‐density lipoprotein (HDL)‐cholesterol level and the risk of breast cancer, there have been some reports of the opposite, and the association therefore remains unclear. HDL is principally known for participating in reverse cholesterol transport and has an inverse relationship with the cardiovascular risk. HDL is heterogeneous, with particles varying in composition, size, and structure, which can be altered under different circumstances, such as inflammation, aging, and certain diseases. It has also been proposed that HDL functionality might have a bearing on the breast cancer. Owing to the potential role of cholesterol in cancer, its reduction using statins, and particularly as an adjuvant during chemotherapy may be useful in the anticancer treatment, and may also be related to the decline in cancer mortality. Reconstituted HDLs have the ability to release chemotherapeutic drugs inside the cell. As a consequence, this may be a novel way to improve therapeutic targeting for the breast cancer on the basis of detrimental impacts of oxidized HDL on cancer development.
... Lee et al. [21] reported that ACAT-1 inhibitor significantly reduced cholesteryl ester storage in lipid droplets and elevated free cholesterol levels, which led to suppression of proliferation and apoptosis of colon cancer cell lines. But Uda [22] found that proliferation of CEM-CCRF cells was slightly affected by ACAT inhibitor; CE content in lipid droplets was significantly higher than those in control cells, and the enzyme activity was continuously inhibited. Antalis et al. [23] found that estrogen receptor negative (ER(−)) breast cancer cells had higher expression of ACAT1 as compared to ER(+)breast cancer cells, and proliferation of ER(−)breast cancer cells was reduced by inhibition of ACAT. ...
Background
Insulin resistant and the progression of cancer is closely related. The aim of this study was to investigate the effect of insulin on the proliferation and migration of colon cancer cells and its underlying mechanism.
Methods
Colon carcinoma tissues from the 80 cases of colon cancer patients were collected. Immunohistochemistry was used to detect the expression of acyl coenzyme A: cholesterol acyltransferase1 (ACAT1), and we analyzed the correlation between hyperglycemia and ACAT1, hyperglycemia and metastasis. CCK8 assay and transwell assay were used to investigate the effect of different concentrations of insulin and ACAT1siRNA on human colon cancer cell line HT-29. ACAT1 mRNA expression and protein level in HT-29 cells were determined by real-time quantitative PCR and western blotting, respectively.
Results
Biopsies from patients with colon carcinoma showed hyperglycemia links ACAT1, lymph nodes metastasis and distant metastasis. Insulin markedly promoted cell proliferation and migration in human colon cancer HT-29 cells. Moreover, ACAT1mRNA expression and protein level were increased by insulin. ACAT1siRNA resulted in a complete inhibition of the ACAT1 mRNA expression. Consequently insulin-triggered cell proliferation and migration on colon cancer cells were inhibited.
Conclusion
The progression of colon cancer has a positive correlation with hyperinsulinemia. Insulin-triggered cell proliferation and metastatic effects on colorectal cancer cells are mediated by ACAT1. Therefore, insulin could promote colon cancer progression by upregulation of ACAT1, which maybe is a potential therapeutic target for colon cancer.
... We tested here if BrA could affect cancer cell proliferation and invasiveness. Cholesteryl esters have been recently identified as tumour promoters by showing they stimulated cancer cells clonogenicity and invasiveness and the inhibition of the cholesteryl esterification of fatty acids (ACAT) has been shown to represent a promising target for cancer management [18,29,30,[35][36][37]. Several pentacyclic triterpenoids including betulinic acid and ursolic acid were reported to inhibit ACAT [38][39][40] suggesting that other pentacyclic triterpenoids could be ACAT inhibitors. ...
Bryonolic acid (BrA) is a pentacyclic triterpene present in several plants used in African 15 traditional medicine such as Anisophyllea dichostyla R. Br.. Here we investigated the in vitro 16 anticancer properties of BrA. We report that BrA inhibits acyl-coA: cholesterol acyl transferase 17 (ACAT) activity in rat liver microsomes in a concentration-dependent manner blocking the 18 biosynthesis of the cholesterol fatty acid ester tumor promoter. We next demonstrated that BrA 19 inhibits ACAT in intact cancer cells with an IC50 of 12.6 ± 2.4 µM. BrA inhibited both clonogenicity 20 and invasiveness of several cancer cell lines, establishing that BrA displays specific anticancer 21 properties. BrA appears to be more potent than the other pentacyclic triterpenes, betulinic acid and 22 ursolic acid studied under similar conditions. The inhibitory effect of BrA was reversed by 23 exogenous addition of cholesteryl oleate, showing that ACAT inhibition is responsible for the 24 anticancer effect of BrA. This report reveals new anticancer properties for BrA. 25
... Consequently, the expression of SR-B1 is upregulated in many cancers including prostate, cervical, breast, and lung cancer [16e18]. Increasing evidence supports HDL as an external source of cholesterol during tumor development [16,19,20]. Furthermore, low levels of HDL-cholesterol have been recorded in patients with cancer [21,22]. ...
Neuroblastoma (NB) is an extra cranial pediatric embryonal tumor most prevalent in children less than 1 year of age. NB accounts for 7% of all pediatric cancers but accounts for 15% of all childhood cancer deaths. Scavenger receptor class B type 1 (SR-B1), a mediator of cellular cholesterol uptake, is overexpressed in and have been linked to the aggressiveness of many cancers. Nevertheless, no studies have so far investigated the relationship between SR-B1 and NB. Elucidation of receptors that promote NB may pave the way for discovery of new therapeutic targets. Here we show that inhibition of SR-B1 reduced cell survival, migration and invasion, and cholesterol content in NB cell lines. Additionally analysis of SR-B1 levels in NB patient biopsies using the R2: Genomics Analysis and Visualization Platform showed that high SR-B1 expression correlated with decreased overall and event-free survival.
... Lee et al. [16] reported that ACAT-1 inhibitor significantly reduced cholesteryl ester storage in lipid droplets and elevated free cholesterol levels, which led to suppression of proliferation and apoptosis of colon cancer cell lines. However, Uda [17] found that proliferation of CEM-CCRF cells was slightly affected by ACAT inhibitor, CE content in lipid droplets was significantly higher than those in control cells, and the enzyme activity was continuously inhibited. Antalis et al. [18] found that estrogen receptor-negative (ER(-)) breast cancer cells had higher expression of ACAT1 as compared to ER(+) breast cancer cells, and proliferation of ER(-) breast cancer cells was reduced by inhibition of ACAT. ...
Background
The main purpose of this study was to explore the antitumor effect and mechanisms of ACAT1 inhibitor combined with CSCs-DC vaccine.
Material/Methods
We isolated HNSCC CSCs and gained CSCs antigens, then used CSCs antigens to load dendritic cells (DC) and generated a CSCs-DC vaccine. We treated mice after surgical excision of established SCC7 tumors with CSCs-DC vaccine and/or ACAT1 inhibitor, and recorded local tumor relapse and host survival. T cells and B cells were harvested from mice treated with CSCs-DC vaccine and/or ACAT1 inhibitor. We tested antibody production and the death rate of CSCs killed by T cells.
Results
The tumors in the combined treatment group were smaller than in all other groups (P<0.01). The average survival time of the combined treatment group was 82 days and was the longest of all groups. Analysis of IgG levels secreted by B cell and CTL activity in spleens of mice found that results of the combined treatment group were the highest, and the results of the CSCs-DC group were lower than in the combined treatment group. The ACAT1 inhibitor group results were lower than in the CSCs-DC group and the combined treatment group results, but higher than in the PBS group, and the difference was statistically significant.
Conclusions
ACAT1 inhibitor enhanced the therapeutic effect of CSCs-DC vaccine in the treatment of the mouse HNSCC postoperative recurrence model. ACAT1 may play an important role in cancer immunotherapy.
... The inhibition of ACAT, the enzyme esterifying cholesterol in the ER, partially blocks cell proliferation in non-malignant cells types [8,9]. However, no such inhibitory effects were observed in the investigated tumor cell lines, even when the drug doses used were remarkably higher than those utilised to completely inhibit cholesterol esterification [10]. It has recently been demonstrated that HDLs deliver the whole CE molecule directly to cancer cells, probably via the plasma membrane protein SR-BI [10,11]. ...
... However, no such inhibitory effects were observed in the investigated tumor cell lines, even when the drug doses used were remarkably higher than those utilised to completely inhibit cholesterol esterification [10]. It has recently been demonstrated that HDLs deliver the whole CE molecule directly to cancer cells, probably via the plasma membrane protein SR-BI [10,11]. Furthermore, CE-HDL uptake increases during endogenous CE deprivation, indicating that this pathway may supply CE when other routes (LDL uptake or CE synthesis) are insufficient to ensure an optimal lipid pool for cellular functions. ...
... Furthermore, CE-HDL uptake increases during endogenous CE deprivation, indicating that this pathway may supply CE when other routes (LDL uptake or CE synthesis) are insufficient to ensure an optimal lipid pool for cellular functions. Although it is unknown whether and how the maintenance of high CE content affects tumor proliferation, these results definitely demonstrate that low plasma levels of HDL, along with the reduction of cholesterol efflux, are a consequence of the active supply of CE-HDL to cancer cells [10,11]. However, low levels of CE-HDL have also been described in several chronic diseases such as sepsis and atherosclerosis [12]. ...
Tumor cells are characterised by a high content of cholesterol esters (CEs), while tumor-bearing patients show low levels of high-density lipoproteins (HDLs). The origin and significance of high CE levels in cancer cell biology has not been completely clarified. Recent evidence that lymphoblastic cells selectively acquire exogenous CE from HDL via the scavenger receptor SR-BI has drawn attention to the additional membrane proteins involved in this pathway. P-glycopotein-MDR1 (P-gp) is a product of the MDR1 gene and confers resistance to antitumor drugs. Its possible role in plasma membrane cholesterol trafficking and CE metabolism has been suggested. In the present study this aspect was investigated in a lymphoblastic cell line selected for MDR1 resistance. CEM were made resistant by stepwise exposure to low (LR) and high (HR) doses of vincristine (VCR). P-gp activity ((3)H-vinblastine), CE content, CE and triglycerides (TG) synthesis ((14)C-oleate), neutral lipids and Dil-HDL uptake (fluorescence), SR-BI, ABCA1 and P-gp protein expression (western blotting) were determined. To better evaluate the relationship between CE metabolism and P-gp activity, the ACAT inhibitor Sandoz-58035 and the P-gp inhibitors progesterone, cyclosporine and verapamil were used. CE content and synthesis were similar in the parental and resistant cells. However, in the latter population, SR-BI protein expression increased, whereas CE-HDL uptake decreased. These changes correlated with the degree of VCR-resistance. As well as reverting MDR1-resistance, the inhibitors of P-gp activity induced the CE-HDL/SR-BI pathway by reactivating membrane cholesterol trafficking. Indeed, CE-HDL uptake, SRBI expression and CE content increased, whereas there was a decrease in cholesterol esterification. These results demonstrated that P-gp overexpression impairs anticancer drug uptake as well as the SR-BI mediated selective CE-HDL uptake. This suggests that these membrane proteins act in an opposite manner on the same transport mechanism. Therefore, the dampening activity of P-gp in this pathway and its reversal by P-gp inhibitors open new strategies for antitumor therapy in drug-resistant tumors.
... Other studies have demonstrated that lipoproteins not only stimulate the growth of breast cancer cells in vitro, but also enhance the aggressiveness of malignant tumors in mouse models [107]. Moreover, the addition of HDL to cell cultures also increased the proliferation of human breast cancer cells [123]. These findings are in line with other reports on the overexpression of scavenger receptor class B type 1 (SR-B1) receptor in cancer cells, suggesting that during carcinogenesis, tumor cells are able to meet their increased need for cholesterol by an HDL mediated process for the removal of cholesterol from peripheral tissues [109]. ...
The metabolic steroid hormones, 17β stradiol (E2) and testosterone play roles in several functions including carbohydrate, lipid and protein metabolism, cellular signaling, cell proliferation, and cancer promotion. Steroid hormones have long been characterized as cell proliferation and differentiation regulators and are closely related to the development of breast and prostate cancers. In addition, cholesterol metabolism, mainly in adipose tissue, leads to the production of steroids and cytokines, thus increasing the risk of metabolic syndrome, obesity, and ER+ breast cancer in postmenopausal women. Moreover, recent studies also show that testosterone and E2 increase the levels of key enzymes of the mevalonate pathway, which lead to post-translational prenylation and farnesylation of numerous proteins in RAS signaling in several cancers, including breast and prostate cancer. There is accumulating evidence both clinically and experimentally suggesting that changes in the metabolism of cholesterol may also have an important role in carcinogenesis. In this regard, the cells treated with mevalonate in culture showed elevated proliferation. Therefore, investigation on cholesterol as a precursor of steroid hormones has led to the identification of cholesterol metabolite effects on breast and prostate cancers. Indeed, recent evidence strongly suggests that the MVA pathway and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCOA) has a crucial regulatory role in cellular proliferation and transformation. Therefore, using mevalonate inhibitors decreases the production of several biologically active downstream products of the mevalonate pathway, including cholesterol. Although for approximately 20 years statins have been identified as anticancer agents, recent studies have sparked some controversy. Therefore, further investigation to evaluate mevalonate - dependent therapeutic agents alone and in combination with other agents is merited. The current review is an attempt to focus on the role of cholesterol as well as E2/testosterone, mevalonate pathway and its inhibitors in breast and prostate tissues during normal and pathological status.
