Influence of cholesterol on cancer progression and therapy

Mayengbam, Shyamananda Singh; Singh, Abhijeet; Pillai, Ajay D.; Bhat, Manoj Kumar

doi:10.1016/j.tranon.2021.101043

Cited by 84 publications

(64 citation statements)

References 217 publications

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“…It was reported that cholesterol accumulation was associated with chemoresistance [ 21 ]. On the other hand, we noticed that Squalene acts as the substrate of Squalene Epoxidase (SQLE) for cholesterol biosynthesis.…”

Section: Resultsmentioning

confidence: 99%

Curcumin sensitizes response to cytarabine in acute myeloid leukemia by regulating intestinal microbiota

Liu

Luo

Chen

et al. 2022

Cancer Chemother Pharmacol

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Purpose To address whether Curcumin has synergistic effect with cytarabine (Ara-C) in treating acute myeloid leukemia (AML). Methods A xenograft AML mouse model was established by injecting HL-60 cells into tail vein of mice to assess the function of Curcumin. Mononuclear cells (MNCs) isolated from AML mice and AML cell lines were used to examine the effect of Curcumin. Metagenomics and metabolomics were used to evaluate the alteration of intestinal microbiota and the change of metabolites in MNCs. Results Curcumin treatment sensitized response to Ara-C in MNCs of AML mice, but had no direct effect on AML cell lines. Metagenomics revealed an alteration of intestinal microbiota with Curcumin treatment, which contributes to sensitized response to Ara-C. Curcumin treatment led to enhanced intestinal intact to sensitize response to Ara-C in AML mice, through reducing mucus degrading bacteria. Metabolomics demonstrated that Curcumin treatment led to decreased cholesterol in MNCs of AML mice. Further study proved that Curcumin treatment resulted in inhibition of SQLE, a key enzyme of cholesterol biosynthesis, to increase sensitivity to Ara-C. Conclusion Curcumin sensitizes response to Ara-C through regulating microbiota, highlighting the importance of intestinal intact strengthening in chemoresistant therapy. Moreover, aiming at cholesterol synthesis is promising in AML treatment.

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Section: Resultsmentioning

confidence: 99%

Curcumin sensitizes response to cytarabine in acute myeloid leukemia by regulating intestinal microbiota

Liu

Luo

Chen

et al. 2022

Cancer Chemother Pharmacol

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“…To maintain continuous proliferation cancer cells may reprogram cholesterol metabolisms, including interaction to extracellular environment through the influx and efflux, de novo synthesis, and multiple intracellular regulatory pathways, among which, reversible conversion of free cholesterol and CE could be the most fast and cost/effective way to obtain free cholesterols. Previously, studies on changes in cholesterol metabolisms in CRC mostly focused on diet intake, systemic level, uptake by cancer cells, and de novo synthesis of free cholesterol [ 19 ]. However, there were scarcely reports on the process of intracellular conversion between free cholesterol and CE.…”

Section: Discussionmentioning

confidence: 99%

Correlation of cholesteryl ester metabolism to pathogenesis, progression and disparities in colorectal Cancer

et al. 2022

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Background Colorectal cancer (CRC) is one of the most common cancers worldwide characterized by disparities in age, gender, race and anatomic sites. The mechanism underlying pathogenesis, progression and disparities of CRC remains unclear. This study aims to reveal the association of expression levels of enzymes related to cholesteryl ester (CE) metabolism with pathogenesis, progression and disparities of CRC. Methods The differences in gene expression levels were analyzed for enzymes in CE synthesis (acyl CoA: cholesterol acyltransferase 1 and 2, ACAT1, and ACAT2), and in CE hydrolysis (neutral cholesterol ester hydrolase, NCEH1 and lysosomal acid lipase, LAL) on TNMplot platform between CRC and normal colorectal tissues (NCT) in a large cohort. The differences in protein expression levels for these enzymes were determined by Immunochemistry (IHC) performed on tissue microarray containing 96 pairs of CRC and benign colorectal tissues (BCT) from different patient populations. The expression level represented as IHC score of each enzyme was compared between CRC and BCT in entire population and populations stratified by race, gender and anatomic sites. Student’s t-test, Fisher exact test and ANOVA were used for data analysis. Significant p value was set at P<0.05. Results The gene expression level of ACAT1 was significantly lower in CRC than in NCT (P = 2.15e-119). The gene expression level of ACAT2 was not statistically different between CRC and NCT. The gene expression level of LIPA (encoding LAL) was significantly higher in CRC than in NCT (P = 2.01e-14). No data was found for the gene expression level of NCEH1. The IHC score of ACAT1was significantly lower in CRC than in BCT in all studied populations and in sub site of colon, but not in that of rectum. The IHC score of ACAT2 was not statistically different between CRC and BCT. IHC score of NCEH1 was significantly higher in CRC than in BCT only in African American (AA) population. The IHC score of LAL was significantly higher in CRC than in BCT in all studied populations and in all sub sites. In addition, decreased ACAT1 in CRC significantly correlated to progression of CRC: the lower IHC score of ACAT1, the more advanced clinical stage of CRC will be. Conclusions This study revealed that altered expression levels in enzymes related to CE metabolism highly correlate to the pathogenesis, clinical progression and disparities of CRC. The results will add revenue in elucidating mechanisms underlying progression of CRC, and shed light on seeking biomarkers and exploring therapeutic targets for CRC in a new direction.

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“…It has been observed that in colorectal cancerous tissue, the levels of cholesterol and triglycerides were reduced and HDL-Cholesterol level increased, indicating that CRC development destroys the physiological balance of lipids and lipoproteins, leading to lipid metabolic disorders [40]. Preclinical and clinical studies have already investigated the role of cholesterol in CRC progression; however, a clear understanding of the molecular mechanism linking these two entities is still lacking [40,41].…”

Section: Discussionmentioning

confidence: 99%

Exploring Serum NMR-Based Metabolomic Fingerprint of Colorectal Cancer Patients: Effects of Surgery and Possible Associations with Cancer Relapse

et al. 2021

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Background: Colorectal cancer (CRC) is the fourth most commonly diagnosed and third most deadly cancer worldwide. Surgery is the main treatment option for early disease; however, a relevant proportion of CRC patients relapse. Here, variations among preoperative and postoperative serum metabolomic fingerprint of CRC patients were studied, and possible associations between metabolic variations and cancer relapse were explored. Methods: A total of 41 patients with stage I-III CRC, planned for radical resection, were enrolled. Serum samples, collected preoperatively (t0) and 4–6 weeks after surgery before the start of any treatment (t1), were analyzed via NMR spectroscopy. NMR data were analyzed using multivariate and univariate statistical approaches. Results: Serum metabolomic fingerprints show differential clustering between t0 and t1 (82–85% accuracy). Pyruvate, HDL-related parameters, acetone, and 3-hydroxybutyrate appear to be the major players in this discrimination. Eight out of the 41 CRC patients enrolled developed cancer relapse. Postoperative, relapsed patients show an increase of pyruvate and HDL-related parameters, and a decrease of Apo-A1 Apo-B100 ratio and VLDL-related parameters. Conclusions: Surgery significantly alters the metabolomic fingerprint of CRC patients. Some metabolic changes seem to be associated with the development of cancer relapse. These data, if validated in a larger cohort, open new possibilities for risk stratification in patients with early-stage CRC.

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Influence of cholesterol on cancer progression and therapy

Cited by 84 publications

References 217 publications

Curcumin sensitizes response to cytarabine in acute myeloid leukemia by regulating intestinal microbiota

Curcumin sensitizes response to cytarabine in acute myeloid leukemia by regulating intestinal microbiota

Correlation of cholesteryl ester metabolism to pathogenesis, progression and disparities in colorectal Cancer

Exploring Serum NMR-Based Metabolomic Fingerprint of Colorectal Cancer Patients: Effects of Surgery and Possible Associations with Cancer Relapse

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