Acyl-Coenzyme A: Cholesterol Acyltransferase Inhibition in Cancer Treatment

Zabielska, Judyta; Śledziński, Tomasz; Stelmańska, Ewa

doi:10.21873/anticanres.13482

Cited by 26 publications

(20 citation statements)

References 46 publications

(59 reference statements)

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“…The outcomes of our experiments demonstrate that intracellular cholesteryl ester levels are influenced by extracellular lipid levels and associates with prostate cancer cell proliferation. Consistent with Yue and colleagues [ 17 ], pharmacological inhibition of ACAT1 reduced both cholesteryl ester levels and cell proliferation, which further adds to the growing body of literature promoting the potential for ACAT1 as an anti-cancer therapeutic target (see reviews [ 54 , 55 ]). Further, elevated ACAT1 expression is associated with reduced time to biochemical recurrence of prostate cancer [ 56 ] as well as progression-free and overall survival.…”

Section: Discussionsupporting

confidence: 70%

Prostate cancer cell proliferation is influenced by LDL-cholesterol availability and cholesteryl ester turnover

et al. 2022

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Background Prostate cancer growth is driven by androgen receptor signaling, and advanced disease is initially treatable by depleting circulating androgens. However, prostate cancer cells inevitably adapt, resulting in disease relapse with incurable castrate-resistant prostate cancer. Androgen deprivation therapy has many side effects, including hypercholesterolemia, and more aggressive and castrate-resistant prostate cancers typically feature cellular accumulation of cholesterol stored in the form of cholesteryl esters. As cholesterol is a key substrate for de novo steroidogenesis in prostate cells, this study hypothesized that castrate-resistant/advanced prostate cancer cell growth is influenced by the availability of extracellular, low-density lipoprotein (LDL)-derived, cholesterol, which is coupled to intracellular cholesteryl ester homeostasis. Methods C4-2B and PC3 prostate cancer cells were cultured in media supplemented with fetal calf serum (FCS), charcoal-stripped FCS (CS-FCS), lipoprotein-deficient FCS (LPDS), or charcoal-stripped LPDS (CS-LPDS) and analyzed by a variety of biochemical techniques. Cell viability and proliferation were measured by MTT assay and Incucyte, respectively. Results Reducing lipoprotein availability led to a reduction in cholesteryl ester levels and cell growth in C4-2B and PC3 cells, with concomitant reductions in PI3K/mTOR and p38MAPK signaling. This reduced growth in LPDS-containing media was fully recovered by supplementation of exogenous low-density lipoprotein (LDL), but LDL only partially rescued growth of cells cultured with CS-LPDS. This growth pattern was not associated with changes in androgen receptor signaling but rather increased p38MAPK and MEK1/ERK/MSK1 activation. The ability of LDL supplementation to rescue cell growth required cholesterol esterification as well as cholesteryl ester hydrolysis activity. Further, growth of cells cultured in low androgen levels (CS-FCS) was suppressed when cholesteryl ester hydrolysis was inhibited. Conclusions Overall, these studies demonstrate that androgen-independent prostate cancer cell growth can be influenced by extracellular lipid levels and LDL-cholesterol availability and that uptake of extracellular cholesterol, through endocytosis of LDL-derived cholesterol and subsequent delivery and storage in the lipid droplet as cholesteryl esters, is required to support prostate cancer cell growth. This provides new insights into the relationship between extracellular cholesterol, intracellular cholesterol metabolism, and prostate cancer cell growth and the potential mechanisms linking hypercholesterolemia and more aggressive prostate cancer.

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Section: Discussionsupporting

confidence: 70%

Prostate cancer cell proliferation is influenced by LDL-cholesterol availability and cholesteryl ester turnover

et al. 2022

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“…To avoid the cytotoxicity of extensive accumulation of free intercellular cholesterol, acyl-coenzyme A-cholesterol acyltransferase (ACAT) transforms cholesterol into cholesterol ester (CE) and stores it in lipid droplets (LDs) [ 34 ]. ACAT2 deficiency dramatically downregulates the absorption rate of cholesterol, activates SREBP, and enhances the transcription of many regulatory proteins, such as HMGCR and lipoprotein receptor (LDLR), to increase cholesterol uptake and synthesis [ 35 , 36 ].…”

Section: Basic Concepts Of Lipids Metabolismmentioning

confidence: 99%

Contradictory roles of lipid metabolism in immune response within the tumor microenvironment

Lei

et al. 2021

J Hematol Oncol

110

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Complex interactions between the immune system and tumor cells exist throughout the initiation and development of cancer. Although the immune system eliminates malignantly transformed cells in the early stage, surviving tumor cells evade host immune defense through various methods and even reprogram the anti-tumor immune response to a pro-tumor phenotype to obtain unlimited growth and metastasis. The high proliferation rate of tumor cells increases the demand for local nutrients and oxygen. Poorly organized vessels can barely satisfy this requirement, which results in an acidic, hypoxic, and glucose-deficient tumor microenvironment. As a result, lipids in the tumor microenvironment are activated and utilized as a primary source of energy and critical regulators in both tumor cells and related immune cells. However, the exact role of lipid metabolism reprogramming in tumor immune response remains unclear. A comprehensive understanding of lipid metabolism dysfunction in the tumor microenvironment and its dual effects on the immune response is critical for mapping the detailed landscape of tumor immunology and developing specific treatments for cancer patients. In this review, we have focused on the dysregulation of lipid metabolism in the tumor microenvironment and have discussed its contradictory roles in the tumor immune response. In addition, we have summarized the current therapeutic strategies targeting lipid metabolism in tumor immunotherapy. This review provides a comprehensive summary of lipid metabolism in the tumor immune response.

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Section: Enzymementioning

confidence: 99%

“…The pool of CoA-SH in the cell is replenished by the enzymes that release it from thioester compounds, e.g., citrate synthase, acyl-coenzyme A: cholesterol acyltransferase (ACAT), many acyland acetyltransferases, acyl-CoA thioesterases, fatty acid synthase (FASN), fatty acid elongase (ELOVL), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), and CPT1 (Table 2), [17][18][19][20][21].Notably, (A) This review summarizes current knowledge of CoA-SH subcellular concentrations, the roles of CoA-SH synthesis and degradation processes and changes in the level of CoA-SH under pathological conditions, such as neurodegenerative diseases, cancer, myopathies, infectious diseases and the genetic make-up of CoA-SH genes. Finally, the beneficial effects of CoA-SH and pantethine (a dimer of the CoA precursor pantetheine) used at pharmacological doses for the treatment of hyperlipidemia are presented.…”

Section: Enzymementioning

confidence: 99%

The Pathophysiological Role of CoA

Czumaj

Szrok-Jurga

Hebanowska

et al. 2020

IJMS

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The importance of coenzyme A (CoA) as a carrier of acyl residues in cell metabolism is well understood. Coenzyme A participates in more than 100 different catabolic and anabolic reactions, including those involved in the metabolism of lipids, carbohydrates, proteins, ethanol, bile acids, and xenobiotics. However, much less is known about the importance of the concentration of this cofactor in various cell compartments and the role of altered CoA concentration in various pathologies. Despite continuous research on these issues, the molecular mechanisms in the regulation of the intracellular level of CoA under pathological conditions are still not well understood. This review summarizes the current knowledge of (a) CoA subcellular concentrations; (b) the roles of CoA synthesis and degradation processes; and (c) protein modification by reversible CoA binding to proteins (CoAlation). Particular attention is paid to (a) the roles of changes in the level of CoA under pathological conditions, such as in neurodegenerative diseases, cancer, myopathies, and infectious diseases; and (b) the beneficial effect of CoA and pantethine (which like CoA is finally converted to Pan and cysteamine), used at pharmacological doses for the treatment of hyperlipidemia.

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Acyl-Coenzyme A: Cholesterol Acyltransferase Inhibition in Cancer Treatment

Cited by 26 publications

References 46 publications

Prostate cancer cell proliferation is influenced by LDL-cholesterol availability and cholesteryl ester turnover

Prostate cancer cell proliferation is influenced by LDL-cholesterol availability and cholesteryl ester turnover

Contradictory roles of lipid metabolism in immune response within the tumor microenvironment

The Pathophysiological Role of CoA

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