The vital role of ATP citrate lyase in chronic diseases

Khwairakpam, Amrita Devi; Banik, Kishore; Girisa, Sosmitha; Shabnam, Bano; Shakibaei, Mehdi; Fan, Li; Arfuso, Frank; Monisha, Javadi; Wang, Hong; Mao, Xinliang; Sethi, Gautam; Kunnumakkara, Ajaikumar B.

doi:10.1007/s00109-019-01863-0

Cited by 52 publications

(42 citation statements)

References 245 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Many different cellular processes such as protein synthesis, autophagy, cell cycle regulation, glycogen metabolism, fatty acid synthesis, nutrient uptake, organization of nuclear proteins, regulation of different hallmarks of cancer like proliferation, survival, angiogenesis, invasion, migration and apoptosis of the cancer cells and the modulation of other signaling pathways such as the nuclear factor kappa-B (NF-κB), extracellular-signal-regulated kinase (ERK), Janus kinase (JAK)-signal transducer and activator of transcription (STAT), are all influenced by the AKT/mTOR signaling pathway [1,[13][14][15][16][17] (Figure 1). The key proteins involved in the regulation of this pathway are phosphoinositide 3-kinase (PI3K), AKT and the mTOR proteins.…”

Section: The Akt/mtor Signaling Pathwaymentioning

confidence: 99%

“…For instance, it regulates the deregulation of GSK-3β that is involved in the process of glycogen synthesis [47]. Besides, the components of this pathway also govern the expression of ATP citrate lyase (ACLY) that is known to be involved in fatty acid synthesis [15,48]. Furthermore, this pathway is also involved in the regulation of glucose-transport-involving proteins such as phosphatidylinositol-4-phosphate 5-kinase (PIP5K) and AS160, glycolysis-involving proteins such as hexokinase and 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 2 (PFKFB2) and the organization of nuclear proteins via Lamin A [49][50][51][52].…”

Section: The Akt/mtor Signaling Pathwaymentioning

confidence: 99%

See 1 more Smart Citation

Targeting AKT/mTOR in Oral Cancer: Mechanisms and Advances in Clinical Trials

Harsha

Banik

Ang

et al. 2020

IJMS

Self Cite

135

110

View full text Add to dashboard Cite

Oral cancer (OC) is a devastating disease that takes the lives of lots of people globally every year. The current spectrum of treatment modalities does not meet the needs of the patients. The disease heterogeneity demands personalized medicine or targeted therapies. Therefore, there is an urgent need to identify potential targets for the treatment of OC. Abundant evidence has suggested that the components of the protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) pathway are intrinsic factors for carcinogenesis. The AKT protein is central to the proliferation and survival of normal and cancer cells, and its downstream protein, mTOR, also plays an indispensable role in the cellular processes. The wide involvement of the AKT/mTOR pathway has been noted in oral squamous cell carcinoma (OSCC). This axis significantly regulates the various hallmarks of cancer, like proliferation, survival, angiogenesis, invasion, metastasis, autophagy, and epithelial-to-mesenchymal transition (EMT). Activated AKT/mTOR signaling is also associated with circadian signaling, chemoresistance and radio-resistance in OC cells. Several miRNAs, circRNAs and lncRNAs also modulate this pathway. The association of this axis with the process of tumorigenesis has culminated in the identification of its specific inhibitors for the prevention and treatment of OC. In this review, we discussed the significance of AKT/mTOR signaling in OC and its potential as a therapeutic target for the management of OC. This article also provided an update on several AKT/mTOR inhibitors that emerged as promising candidates for therapeutic interventions against OC/head and neck cancer (HNC) in clinical studies.

show abstract

Section: The Akt/mtor Signaling Pathwaymentioning

confidence: 99%

Section: The Akt/mtor Signaling Pathwaymentioning

confidence: 99%

Targeting AKT/mTOR in Oral Cancer: Mechanisms and Advances in Clinical Trials

Harsha

Banik

Ang

et al. 2020

IJMS

Self Cite

135

110

View full text Add to dashboard Cite

show abstract

“…Moreover, PDK2 gene disruption in lung cancer cells have been reported to increase cell sensitivity to Paclitaxel chemotherapeutic agent ( 91 ). Part of METABLOC, HCA is an inhibitor of ATP-citrate lyase (ACL) to prevent lipogenesis ( 82 , 92 , 93 ). Finally, we used metformin, which is used in type II diabetes ( 94 ) and reported as inhibitor of complex I ( 95 – 97 ), and diclofenac, which is an anti-inflammatory and inhibitor of lactate dehydrogenase (LDH) and of the transporter of monocarboxylate (MCT1) ( 98 , 99 ).…”

Section: Metabolic Therapies For Cancer Treatmentmentioning

confidence: 99%

Targeting Mitochondrial Singlet Oxygen Dynamics Offers New Perspectives for Effective Metabolic Therapies of Cancer

2020

View full text Add to dashboard Cite

The occurrence of mitochondrial respiration has allowed evolution toward more complex and advanced life forms. However, its dysfunction is now also seen as the most probable cause of one of the biggest scourges in human health, cancer. Conventional cancer treatments such as chemotherapy, which mainly focus on disrupting the cell division process, have shown being effective in the attenuation of various cancers but also showing significant limits as well as serious sides effects. Indeed, the idea that cancer is a metabolic disease with mitochondria as the central site of the pathology is now emerging, and we provide here a review supporting this "novel" hypothesis re-actualizing past century Otto Warburg's thoughts. Our conclusion, while integrating literature, is that mitochondrial activity and, in particular, the activity of cytochrome c oxidase, complex IV of the ETC, plays a fundamental role in the effectiveness or non-effectiveness of chemotherapy, immunotherapy and probably radiotherapy treatments. We therefore propose that cancer cells mitochondrial singlet oxygen (1 O 2) dynamics may be an efficient target for metabolic therapy development.

show abstract

“…In the cytosol, ACLY provides acetyl-CoA, which sustains some biosynthetic processes, including lipid synthesis and acetylation of both histone and non-histone proteins. In cancer cells, to prevent the suppression of glycolysis, citrate is rapidly converted into OAA and acetyl-CoA by ACLY, which is overexpressed (Zaidi et al, 2012;Khwairakpam et al, 2015;Khwairakpam et al, 2020). The conversion of OAA into malate by malate dehydrogenase produces NAD + to sustain glycolysis (Gatenby and Gillies, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…Considering the crucial role of citrate to supply the acetyl-CoA pool for fatty acid synthesis and histone acetylation in tumors (Wellen et al, 2009;Lee et al, 2014;Khwairakpam et al, 2020), in the present study, we assessed the effect of exogenous citrate supplementation on both ACLY expression and histone H4 acetylation in hepatoma cells (HepG2). All the experiments were performed at high and low glucose concentrations in order to verify that the observed effects are attributable to the involvement of citrate into glucose metabolism as well as to make a quantitative assessment.…”

Section: Introductionmentioning

confidence: 99%

Extracellular Citrate Is a Trojan Horse for Cancer Cells

Petillo

Abruzzese

Koshal

et al. 2020

Front. Mol. Biosci.

View full text Add to dashboard Cite

The first intermediate in the mitochondrial tricarboxylic acid (TCA) cycle is citrate, which is essential and acts as a metabolic regulator for glycolysis, TCA cycle, gluconeogenesis, and fatty acid synthesis. Within the cytosol, citrate is cleaved by ATP citrate lyase (ACLY) into oxaloacetate (OAA) and acetyl-CoA; OAA can be used for neoglucogenesis or in the TCA cycle, while acetyl-CoA is the precursor of some biosynthetic processes, including the synthesis of fatty acids. Accumulating evidence suggests that citrate is involved in numerous physiological and pathophysiological processes such as inflammation, insulin secretion, neurological disorders, and cancer. Considering the crucial role of citrate to supply the acetyl-CoA pool for fatty acid synthesis and histone acetylation in tumors, in this study we evaluated the effect of citrate added to the growth medium on lipid deposition and histone H4 acetylation in hepatoma cells (HepG2). At low concentration, citrate increased both histone H4 acetylation and lipid deposition; at high concentration, citrate inhibited both, thus suggesting a crucial role of acetyl-CoA availability, which prompted us to investigate the effect of citrate on ACLY. In HepG2 cells, the expression of ACLY is correlated with histone acetylation, which, in turn, depends on citrate concentration. A decrease in H4 acetylation was also observed when citrate was added at a high concentration to immortalized human hepatic cells, whereas ACLY expression was unaffected, indicating a lack of control by histone acetylation. Considering the strong demand for acetyl-CoA but not for OAA in tumor cells, the exogenous citrate would behave like a trojan horse that carries OAA inside the cells and reduces ACLY expression and cellular metabolism. In addition, this study confirmed the already reported dual role of citrate both as a promoter of cell proliferation (at lower concentrations) and as an anticancer agent (at higher concentrations), providing useful tips on the use of citrate for the treatment of tumors.

show abstract

The vital role of ATP citrate lyase in chronic diseases

Cited by 52 publications

References 245 publications

Targeting AKT/mTOR in Oral Cancer: Mechanisms and Advances in Clinical Trials

Targeting AKT/mTOR in Oral Cancer: Mechanisms and Advances in Clinical Trials

Targeting Mitochondrial Singlet Oxygen Dynamics Offers New Perspectives for Effective Metabolic Therapies of Cancer

Extracellular Citrate Is a Trojan Horse for Cancer Cells

Contact Info

Product

Resources

About