ATP citrate lyase is increased in human breast cancer, depletion of which promotes apoptosis

Wang, Diyu; Yin, Lei; Wei, Jinrong; Yang, Zhi‐Xue; Jiang, Guoqin

doi:10.1177/1010428317698338

Cited by 48 publications

(37 citation statements)

References 47 publications

(60 reference statements)

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“…Previous research has reported that the inhibition of ACC reduces tumor growth of pancreatic cancer xenografted in animal models [11] and increases apoptosis in glioblastoma cell lines [12]. Following small interfering RNAmediated inhibition of ACLY in MCF-7 breast cancer cells, cell viability was suppressed and cell apoptosis was increased [13]. Additional supporting evidence to verify the DNL pathway in regulating cancer cell viability has been shown where the inhibition of FASN by FASN inhibitor-alcohol extract of clove suppressed the S-phase DNA replication of HepG2 cells [14].…”

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confidence: 97%

Suppressed de novo lipogenesis by plasma membrane citrate transporter inhibitor promotes apoptosis in HepG2 cells

et al. 2018

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Suppression of the expression or activities of enzymes that are involved in the synthesis of de novo lipogenesis ( DNL ) in cancer cells triggers cell death via apoptosis. The plasma membrane citrate transporter ( PMCT ) is the initial step that translocates citrate from blood circulation into the cytoplasm for de novo long‐chain fatty acids synthesis. This study investigated the antitumor effect of the PMCT inhibitor ( PMCT i) in inducing apoptosis by inhibiting the DNL pathway in HepG2 cells. The present findings showed that PMCT i reduced cell viability and enhanced apoptosis through decreased intracellular citrate levels, which consequently caused inhibition of fatty acid and triacylglycerol productions. Thus, as a result of the reduction in fatty acid synthesis, the activity of carnitine palmitoyl transferase‐1 ( CPT ‐1) was suppressed. Decreased CPT ‐1 activity also facilitated the disruption of mitochondrial membrane potential (ΔΨm) leading to stimulation of apoptosis. Surprisingly, primary human hepatocytes were not affected by PMCT i. Increased caspase‐8 activity as a consequence of reduction in fatty acid synthesis was also found to cause disruption of ΔΨm. In addition, apoptosis induction by PMCT i was associated with an enhanced reactive oxygen species generation. Taken together, we suggest that inhibition of the DNL pathway following reduction in citrate levels is an important regulator of apoptosis in HepG2 cells via suppression of CPT ‐1 activity. Thus, targeting the DNL pathway mediating CPT ‐1 activity by PMCT i may be a selective potential anticancer therapy.

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confidence: 97%

Suppressed de novo lipogenesis by plasma membrane citrate transporter inhibitor promotes apoptosis in HepG2 cells

et al. 2018

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“…In the latter case, the dependence of tumors on glucose for energy makes ACLY inhibition especially appealing. ACLY knockdown can drastically decrease cancer cell proliferation without significantly affecting nearby healthy tissue (30,31). ACLY may also be a target for anti-aging studies, because decreased nucleocytosolic acetyl-…”

Section: Discussionmentioning

confidence: 99%

ATP-citrate lyase multimerization is required for coenzyme-A substrate binding and catalysis

Bazilevsky¹,

Affronti

Wei

et al. 2019

Journal of Biological Chemistry

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Edited by Joel M. Gottesfeld ATP-citrate lyase (ACLY) is a major source of nucleocytosolic acetyl-CoA, a fundamental building block of carbon metabolism in eukaryotes. ACLY is aberrantly regulated in many cancers, cardiovascular disease, and metabolic disorders. However, the molecular mechanisms determining ACLY activity and function are unclear. To this end, we investigated the role of the uncharacterized ACLY C-terminal citrate synthase homology domain in the mechanism of acetyl-CoA formation. Using recombinant, purified ACLY and a suite of biochemical and biophysical approaches, including analytical ultracentrifugation, dynamic light scattering, and thermal stability assays, we demonstrated that the C terminus maintains ACLY tetramerization, a conserved and essential quaternary structure in vitro and likely also in vivo. Furthermore, we show that the C terminus, only in the context of the full-length enzyme, is necessary for full ACLY binding to CoA. Together, we demonstrate that ACLY forms a homotetramer through the C terminus to facilitate CoA binding and acetyl-CoA production. Our findings highlight a novel and unique role of the C-terminal citrate synthase homology domain in ACLY function and catalysis, adding to the understanding of the molecular basis for acetyl-CoA synthesis by ACLY. This newly discovered means of ACLY regulation has implications for the development of novel ACLY modulators to target acetyl-CoA-dependent cellular processes for potential therapeutic use.All three domains of life utilize acetyl-CoA as an essential metabolite for carbon transport. Acetyl-CoA is necessary for glycolysis, de novo lipogenesis, cholesterol synthesis, and protein acetylation (1). The dysregulation of this metabolite is an omnipresent feature and crucial component of diabetes, hypercholesterolemia, and oncogenesis (2). Among the majority of 2 The abbreviations used are: ACLY, ATP-citrate lyase; CS, citrate synthase; CSHD, citrate synthase homology domain; DSC, differential scanning calo-

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“…It is anticipated that 25% of the world's population will have at least one type of cancer in 2030 (Talib, Al‐hadid, Ali, Al‐Yasari, & Ali, 2018). Breast cancer (BC) is one of the major causes of female cancer‐related death (Wang, Yin, Wei, Yang, & Jiang, 2017). It is estimated that 3,131,440 females living in the United States have BC (Talib et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…It is widely accepted that cancer is not only a genetic disease but also a metabolic disorder (Wang et al, 2017). Metabolic reprogramming is one of the hallmarks of cancer cells that supply the energy and the (macro‐) molecules required for their rapid proliferation (Brohée et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have demonstrated that cancer cells have changes in various features of lipid metabolism (Qu et al, 2017), and that fatty acid (FA) synthesis is necessary during the growth and proliferation of cancer cells (Wang et al, 2017). FAs are essential for the synthesis of cell membrane and are involved in signaling (Currie, Schulze, Zechner, Walther, & Farese, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Expression and clinicopathological significance of lipin‐1 in human breast cancer and its association with p53 tumor suppressor gene

Dinarvand

Khanahmad

Hakimian

et al. 2020

Journal Cellular Physiology

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Breast cancer (BC) is an important cause of female cancer‐related death. It has recently been demonstrated that metabolic disorders including lipid metabolism are a hallmark of cancer cells. Lipin‐1 is an enzyme that displays phosphatidate phosphatase activity and regulates the rate‐limiting step in the pathway of triglycerides and phospholipids synthesis. The objective of this study was to evaluate lipin‐1 expression, its prognostic significance, and its correlation with p53 tumor suppressor in patients with BC. In this study, 55 pairs of fresh samples of BC and adjacent noncancerous tissue were used to analyze lipin‐1, using quantitative real‐time polymerase chain reaction and immunohistochemistry (IHC) staining. The expression of other clinicopathological variables and p53 was also examined using IHC technique. The cell migration was studied in MCF‐7 and MDA‐MB231 cells following the inhibition of lipin‐1 by propranolol. Our results show that the relative expression of lipin‐1 messenger RNA was significantly higher in BC tissues compared with the adjacent normal tissue and its inhibition reduced cell migration in cancer cells. This upregulation was negatively correlated with histological grade of tumor and p53 status (p = .001 and p = .034) respectively and positively correlated with the tumor size (p = .006). Our results also seem to indicate that the high lipin‐1 expression is related to a good prognosis in patients with BC. The expression of lipin‐1 may be considered as a novel independent prognostic factor. The inhibition of lipin‐1 may also have therapeutic significance for patients with BC. The correlation between lipin‐1 and p53 confirms the role of p53 in the regulation of lipid metabolism in cancer cells.

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ATP citrate lyase is increased in human breast cancer, depletion of which promotes apoptosis

Cited by 48 publications

References 47 publications

Suppressed de novo lipogenesis by plasma membrane citrate transporter inhibitor promotes apoptosis in HepG2 cells

Suppressed de novo lipogenesis by plasma membrane citrate transporter inhibitor promotes apoptosis in HepG2 cells

ATP-citrate lyase multimerization is required for coenzyme-A substrate binding and catalysis

Expression and clinicopathological significance of lipin‐1 in human breast cancer and its association with p53 tumor suppressor gene

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