An Essential Requirement for the SCAP/SREBP Signaling Axis to Protect Cancer Cells from Lipotoxicity

Williams, Kevin J.; Argus, Joseph P.; Zhu, Yue; Wilks, Moses Q.; Marbois, Beth N.; York, Autumn G.; Kidani, Yoko; Pourzia, Alexandra L.; Akhavan, David; Lisiero, Dominique N.; Komisopoulou, Evangelia; Henkin, Amy H.; Soto, Horacio; Chamberlain, Brian T.; Vergnes, Laurent; Jung, Michael E.; Torres, Jorge Z.; Liau, Linda M.; Christofk, Heather R.; Prins, Robert M.; Mischel, Paul S.; Reue, Karen; Graeber, Thomas G.; Bensinger, Steven J.

doi:10.1158/0008-5472.can-13-0382-t

Cited by 165 publications

(146 citation statements)

References 36 publications

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“…SCD1 is suggested be a major driver of fatty acid synthesis from glucose (46) and has also been shown to help negotiate cellular stress, with SCD1 inhibition leading to saturated fatty acid accumulation, toxicity, and endoplasmic reticulum stress (40,47,48). This is likely to be of particular importance in the cancer phenotype where levels of saturated fatty acid synthesis are often high (15,16).…”

Section: Discussionmentioning

confidence: 99%

Drug Redeployment to Kill Leukemia and Lymphoma Cells by Disrupting SCD1-Mediated Synthesis of Monounsaturated Fatty Acids

et al. 2015

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The redeployed drug combination of bezafibrate and medroxyprogesterone acetate (designated BaP) has potent in vivo anticancer activity in acute myelogenous leukemia (AML) and endemic Burkitt lymphoma (eBL) patients; however, its mechanism-of-action is unclear. Given that elevated fatty acid biosynthesis is a hallmark of many cancers and that these drugs can affect lipid metabolism, we hypothesized that BaP exerts anticancer effects by disrupting lipogenesis. We applied mass spectrometry-based lipidomics and gene and protein expression measurements of key lipogenic enzymes [acetyl CoA carboxylase 1 (ACC1), fatty acid synthase (FASN), and stearoyl CoA desaturase 1 (SCD1)] to AML and eBL cell lines treated with BaP. BaP treatment decreased fatty acid and phospholipid biosynthesis from 13 C D-glucose. The proportion of phospholipid species with saturated and monounsaturated acyl chains was also decreased after treatment, whereas those with polyunsaturated chains increased. BaP decreased SCD1 protein levels in each cell line (0.46-to 0.62-fold; P < 0.023) and decreased FASN protein levels across all cell lines (0.87-fold decrease; P ¼ 1.7 Â 10 À4 ). Changes to ACC1 protein levels were mostly insignificant. Supplementation with the SCD1 enzymatic product, oleate, rescued AML and e-BL cells from BaP cell killing and decreased levels of BaP-induced reactive oxygen species, whereas supplementation with the SCD1 substrate (and FASN product), palmitate, did not rescue cells. In conclusion, these data suggest that the critical anticancer actions of BaP are decreases in SCD1 levels and monounsaturated fatty acid synthesis. To our knowledge, this is the first time that clinically available antileukemic and antilymphoma drugs targeting SCD1 have been reported. Cancer Res; 75(12); 2530-40. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 99%

Drug Redeployment to Kill Leukemia and Lymphoma Cells by Disrupting SCD1-Mediated Synthesis of Monounsaturated Fatty Acids

et al. 2015

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“…SCAP is a regulatory element binding protein (SREBP) cleavage-activating protein (SCAP). SCAP gene plays important role as a sterol sensor (Espenshade, 2006) as well as a transcriptional regulator of lipid metabolism and cellular growth (Williams et al, 2013). Previous research has shown that androgen (therapeutics agent used for advanced prostate cancer) has increased the expression of SCAP suggesting lipogenic effect of this agent in prostate cancer cells (Heemers et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Expression Profile of Genes Modulated by Aloe emodin in Human U87 Glioblastoma Cells

Haris

Ismail²,

Idris³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Glioblastoma, the most aggressive and malignant form of glioma, appears to be resistant to various chemotherapeutic agents. Hence, approaches have been intensively investigated to targeti specific molecular pathways involved in glioblastoma development and progression. Aloe emodin is believed to modulate the expression of several genes in cancer cells. We aimed to understand the molecular mechanisms underlying the therapeutic effect of Aloe emodin on gene expression profiles in the human U87 glioblastoma cell line utilizing microarray technology. The gene expression analysis revealed that a total of 8,226 gene alterations out of 28,869 genes were detected after treatment with 58.6 µg/ml for 24 hours. Out of this total, 34 genes demonstrated statistically significant change (p<0.05) ranging from 1.07 to 1.87 fold. The results revealed that 22 genes were up-regulated and 12 genes were down-regulated in response to Aloe emodin treatment. These genes were then grouped into several clusters based on their biological functions, revealing induction of expression of genes involved in apoptosis (programmed cell death) and tissue remodelling in U87 cells (p<0.01). Several genes with significant changes of the expression level e.g. SHARPIN, BCAP31, FIS1, RAC1 and TGM2 from the apoptotic cluster were confirmed by quantitative real-time PCR (qRT-PCR). These results could serve as guidance for further studies in order to discover molecular targets for the cancer therapy based on Aloe emodin treatment.

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“…One microliter of sample was injected in split mode. Full oven program and MS settings are available upon request (55). MS detector was run in SIM mode.…”

Section: Gc/ms Analysismentioning

confidence: 99%

Transintestinal transport of the anti-inflammatory drug 4F and the modulation of transintestinal cholesterol efflux

Meriwether

Sulaiman

Wagner

et al. 2016

Journal of Lipid Research

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Increasing evidence, both direct and indirect, indicates that the small intestine (SI) may be an important modulator of atherosclerosis. As a result, the SI offers promising therapeutic targets for the prevention and treatment of this disease.The SI is linked to atherosclerosis in at least four respects. First, intestinal inflammation in the form of inflammatory bowel disease (IBD) has been linked to an increased prevalence of early stage vascular disease in patients without the classical cardiovascular risk factors (1-3). Second, our own recent research has established a link between aberrant levels of lipid signals in the SI and both dyslipidemia and atherosclerosis. Intestinally derived unsaturated lysophosphatidic acids (LPAs) and eicosanoids can both induce dyslipidemia as well as systemic inflammation in LDL receptor null (LDLR / ) mice (4, 5). Dietary LPA can also induce atherogenesis (6), and the levels of unsaturated LPAs in the SI correlate with the extent of atherosclerosis in LDLR / mice fed a Western diet (WD) (7). Third, the SI is an important source of apoAI (8), and at least in mice 30% of the steady-state plasma HDLcholesterol pool is derived from the SI (9). Moreover, while HDL can interrupt atherogenesis by preventing oxidative Abstract The site and mechanism of action of the apoA-I mimetic peptide 4F are incompletely understood. Transintestinal cholesterol efflux (TICE) is a process involved in the clearance of excess cholesterol from the body. While TICE is responsible for at least 30% of the clearance of neutral sterols from the circulation into the intestinal lumen, few pharmacological agents have been identified that modulate this pathway. We show first that circulating 4F selectively targets the small intestine (SI) and that it is predominantly transported into the intestinal lumen. This transport of 4F into the SI lumen is transintestinal in nature, and it is modulated by TICE. We also show that circulating 4F increases reverse cholesterol transport from macrophages and cholesterol efflux from lipoproteins via the TICE pathway. We identify the cause of this modulation of TICE either as 4F being a cholesterol acceptor with respect to enterocytes, from which 4F enhances cholesterol efflux, or as 4F being an intestinal chaperone with respect to TICE. Our results assign a novel role for 4F as a modulator of the TICE pathway and suggest that the anti-inflammatory functions of 4F may be a partial consequence of the codependent intestinal transport of both 4F and cholesterol.

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An Essential Requirement for the SCAP/SREBP Signaling Axis to Protect Cancer Cells from Lipotoxicity

Cited by 165 publications

References 36 publications

Drug Redeployment to Kill Leukemia and Lymphoma Cells by Disrupting SCD1-Mediated Synthesis of Monounsaturated Fatty Acids

Drug Redeployment to Kill Leukemia and Lymphoma Cells by Disrupting SCD1-Mediated Synthesis of Monounsaturated Fatty Acids

Expression Profile of Genes Modulated by Aloe emodin in Human U87 Glioblastoma Cells

Transintestinal transport of the anti-inflammatory drug 4F and the modulation of transintestinal cholesterol efflux

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