The anticancer gene ORCTL3 targets stearoyl-CoA desaturase-1 for tumour-specific apoptosis

AbuAli, Ghada; Chaisaklert, Wanwisa; Stelloo, Ellen; Pazarentzos, Evangelos; Hwang, Ming-Shih; Ding, Qize; Harding, Scott; Al-Rubaish, Abdullah M.; Alzahrani, Alhusain J.; Al-Ali, Amein K.; Sanders, Tom; Aboagye, Eric O.; Grimm, Stefan

doi:10.1038/onc.2014.93

Cited by 11 publications

(3 citation statements)

References 35 publications

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“…Inhibition of SCD1 activity, either by certain genetic manipulations or by some pharmaceuticals (see Figure 5 ), decreases the fatty acid desaturation index. Such inhibition has been shown to exhibit potent anti-tumor effects in different forms of cancer by affecting various aspects of cancer initiation, promotion and progression [ 5 , 163 , 180 , 184 , 186 , 188 , 212 - 219 ]. Recent studies have suggested two different types of mechanisms through which such inhibition of SCD1 and the resulting decrease of the fatty acid desaturation index (i.e.…”

Section: A Novel Approach To Discovering Selective Anti-tumor Pharmacmentioning

confidence: 99%

A novel approach to the discovery of anti-tumor pharmaceuticals: searching for activators of liponecrosis

et al. 2015

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A recently conducted chemical genetic screen for pharmaceuticals that can extend longevity of the yeast Saccharomyces cerevisiae has identified lithocholic acid as a potent anti-aging molecule. It was found that this hydrophobic bile acid is also a selective anti-tumor chemical compound; it kills different types of cultured cancer cells if used at concentrations that do not compromise the viability of non-cancerous cells. These studies have revealed that yeast can be successfully used as a model organism for high-throughput screens aimed at the discovery of selectively acting anti-tumor small molecules. Two metabolic traits of rapidly proliferating fermenting yeast, namely aerobic glycolysis and lipogenesis, are known to be similar to those of cancer cells. The mechanisms underlying these key metabolic features of cancer cells and fermenting yeast have been established; such mechanisms are discussed in this review. We also suggest how a yeast-based chemical genetic screen can be used for the high-throughput development of selective anti-tumor pharmaceuticals that kill only cancer cells. This screen consists of searching for chemical compounds capable of increasing the abundance of membrane lipids enriched in unsaturated fatty acids that would therefore be toxic only to rapidly proliferating cells, such as cancer cells and fermenting yeast.

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Section: A Novel Approach To Discovering Selective Anti-tumor Pharmacmentioning

confidence: 99%

A novel approach to the discovery of anti-tumor pharmaceuticals: searching for activators of liponecrosis

et al. 2015

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“…In the MDA‐MB‐231 cancer cell lines, SCD1 silencing inhibits β‐catenin signaling and impairs the epithelial to mesenchymal transition‐like behavior of the cells . The anticancer gene ORCTL3 targets the SCD1 enzyme to exert tumor‐specific effects leading to the induction of apoptosis in renal cancer cells in vitro, in vivo, and ex vivo . In acute myelogenous leukemia and endemic Burkitt's‐lymphoma‐derived cell lines, anti‐leukemic and anti‐lymphoma drugs (designated BaP) exert an anticancer action by slowing de novo fatty acid biosynthesis via the downregulation of SCD1‐mediated MUFA synthesis .…”

Section: Enzymes Involved In Fatty Acid Biosynthesis and Degradationmentioning

confidence: 99%

Fatty acid metabolism and prospects for targeted therapy of cancer

Chen

2017

Euro J Lipid Sci & Tech

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Fatty acids are fundamental substrates required for energy storage, synthesis of membranes, generation of signaling molecules and lipid droplet formation in cancer cells. High levels of fatty acid metabolic activity are one of the most aberrant metabolic alterations in cancer cells. The de novo fatty acid synthesis pathway is the primary source of fatty acids in cancer cells, but cancer cells can also acquire fatty acids through the lipolytic pathway, which helps cells survive and maintain their invasiveness. Key enzymes, including ATP‐citrate lyase (ACLY), fatty acid synthase (FASN), acetyl‐coenzyme A (CoA) carboxylase (ACC), stearoyl‐CoA desaturase 1(SCD1) and monoacylglycerol lipase (MAGL), which are involved in fatty acid synthesis and degradation, are overexpressed in cancer cells. The alterations in fatty acid metabolomics in different cancers, at different stages of cancer, and in different tissues are clinically significant. This review focuses on current research into fatty acid metabolism to explore new targets against the fatty acid metabolic pathways for anticancer therapy. Practical applications: High levels of fatty acid metabolic activity are one of the most aberrant metabolic alterations in cancer cells. Reprogramming in fatty acid metabolism plays an important role in energy storage, membrane proliferation, the generation of signaling molecules and lipid droplet formation in cancer cells. Understanding the mechanism of regulated the fatty acid metabolic pathways in cancer would reveal novel targeted therapy of cancer. To maintain the balance of the free fatty acid composition and thus promote cancer cell growth, survival, and progression, the levels of de novo fatty acid synthesis and degradation are elevated. Therefore, the targeted inhibition of key enzymes involved in fatty acid metabolism, such as ACLY, ACC, FASN, MAGL, and SCD1, and the utilization of anticancer exogenous fatty acids might constitute effective cancer therapies. ATP, adenosine‐triphosphate; DAG, diacylglycerol; IHBTIS, inhibitors; MUFA, monounsaturated fatty acids; MAG, monoacylglycerol; TAG triacylglycerol.

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“…ere is accumulating evidence that aberrant expression of the stearoyl-CoA desaturase is also involved in disease; in mammals, an anticancer gene ORCTL3 was identified that could cause apoptosis in certain transformed cells [5]. Later research identified the target of ORTLC3 as the stearoyl-CoA desaturase [6]. And in yeast, overexpression of stearoyl-CoA desaturase leads to invasive growth [7].…”

Section: Introductionmentioning

confidence: 99%

A Transcriptional Regulatory System of theS. cerevisiae OLE1Gene Responds to Fatty Acid Species and Intracellular Amount, and not Simply Membrane Status

et al. 2020

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We examined the effects of unsaturated fatty acid (UFA) species and their concentration on the expression of OLE1, which encodes the stearoyl CoA desaturase, in Saccharomyces cerevisiae. We controlled the amount of UFA taken up by the cell by varying the concentration of tergitol in the medium. When cultured with 1 mM fatty acid in 0.1% tergitol, cells took up much more fatty acid than when cultured with the same concentration of fatty acid at 1% tergitol, although the amount incorporated was dependent on UFA species. For each fatty acid tested, we found that the higher uptake (0.1% tergitol condition) had a stronger impact on OLE1 regulation. A principal product of the desaturase 16:1∆9, and the nonnative UFA 18:2∆9,12, most strongly repressed the reporter construct OLE1-lacZ transcription, while the other major product of the desaturase, 18:1∆9, and the nonnative UFA 17:1∆10 caused a more diminished response. Based on these results, our initial hypothesis was that OLE1 was regulated in response to membrane fluidity; however, subsequent work does not support that idea; we have found that conditions that affect membrane fluidity such as growth temperature and growth with saturated or trans fatty acid supplementation, do not regulate OLE1 in the direction predicted by fluidity changes. We conclude that at least one signal that regulates OLE1 transcriptional expression is most likely based on the fatty acids themselves.

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The anticancer gene ORCTL3 targets stearoyl-CoA desaturase-1 for tumour-specific apoptosis

Cited by 11 publications

References 35 publications

A novel approach to the discovery of anti-tumor pharmaceuticals: searching for activators of liponecrosis

A novel approach to the discovery of anti-tumor pharmaceuticals: searching for activators of liponecrosis

Fatty acid metabolism and prospects for targeted therapy of cancer

A Transcriptional Regulatory System of theS. cerevisiae OLE1Gene Responds to Fatty Acid Species and Intracellular Amount, and not Simply Membrane Status

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