Efficient Use of Exogenous Isoprenols for Protein Isoprenylation by MDA-MB-231 Cells Is Regulated Independently of the Mevalonate Pathway

Onono, Fredrick O.; Subramanian, Thangaiah; Sunkara, Manjula; Subramanian, Karunai Leela; Spielmann, H. Peter; Morris, Andrew J.

doi:10.1074/jbc.m113.482307

Cited by 16 publications

(22 citation statements)

References 25 publications

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“…For hepatic TG and cholesterol measurements, liver tissues were collected from male NT +/+ and NT −/− mice fed HFD for 24 weeks after weaning; TG and cholesterol were extracted as described previously 39 and analyzed by LC-MS coupled with electrospray ionization tandem using stable isotope dilution 40 performed on AB Sciex 4000 Q-Trap instruments. Fasting plasma glucose was analyzed using a Glucose Colorimetric Assay Kit II (BioVision) and insulin using a Mouse Insulin ELISA kit (Mercodia Inc, Winston Salem, NC).…”

Section: Methodsmentioning

confidence: 99%

An obligatory role for neurotensin in high-fat-diet-induced obesity

Song

Zaytseva

et al. 2016

Nature

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227

237

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Obesity and its associated comorbidities (e.g., diabetes mellitus and hepatic steatosis) contribute to approximately 2.5 million deaths annually1 and are among the most prevalent and challenging conditions confronting the medical profession2,3. Neurotensin (NT), a 13-amino acid peptide predominantly localized in specialized enteroendocrine (EE) cells of the small bowel4 and released by fat ingestion5, facilitates fatty acid (FA) translocation in rat intestine6, and stimulates growth of various cancers7; the effects of NT are mediated through three known NT receptors (NTR1, 2 and 3)8. Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with increased risk of diabetes, cardiovascular disease and mortality9; however, a role for NT as a causative factor in these diseases is unknown. Here, we show that NT-deficient mice demonstrate significantly reduced intestinal fat absorption and are protected from obesity, hepatic steatosis and insulin resistance associated with high fat consumption. We further demonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates FA absorption in mice and in cultured intestinal cells, and that this occurs through a mechanism involving NTR1 and NTR3/sortilin. Consistent with the findings in mice, expression of NT in Drosophila midgut EE cells results in increased lipid accumulation in the midgut, fat body, and oenocytes (specialized hepatocyte-like cells) and decreased AMPK activation. Remarkably, in humans, we show that both obese and insulin-resistant subjects have elevated plasma concentrations of pro-NT, and in longitudinal studies among non-obese subjects, high levels of pro-NT denote a doubling of the risk of developing obesity later in life. Our findings directly link NT with increased fat absorption and obesity and suggest that NT may provide a prognostic marker of future obesity and a potential target for prevention and treatment.

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Section: Methodsmentioning

confidence: 99%

An obligatory role for neurotensin in high-fat-diet-induced obesity

Song

Zaytseva

et al. 2016

Nature

Self Cite

227

237

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“…It will be interesting in the future to reveal why PMVK is preferentially downregulated in basal-like TNBCs and whether its downregulation affects the mevalonate pathway in basal-like TNBCs. Although the role of the mevalonate pathway in basal-like TNBC is unclear, a related study showed that MDA-MB-231 cells efficiently used exogenous isoprenols for protein isoprenylation in independent of the mevalonate pathway [33]. This clue suggests that TNBC cells may be capable of using exogenous isoprenols for their survival and growth even though endogenous isoprenoid biosynthesis is limited.…”

Section: Resultsmentioning

confidence: 99%

FOXF2 differentially regulates expression of metabolic genes in non-cancerous and cancerous breast epithelial cells

2018

Trends Diabetes Metab

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Forkhead box F2 (FOXF2) functions as a transcription factor and is critically involved in programming organogenesis and regulating epithelial-to-mesenchymal transition (EMT) and cell proliferation. We recently have revealed that FOXF2 can exert distinct functional effects on different molecular subtypes of breast cancer. We found that FOXF2 expression is epigenetically silenced in luminal breast cancers due to its tumor-suppressive role in DNA replication regulation. In contrast, FOXF2 is overexpressed in basal-like triple-negative breast cancers (TNBCs) due to its oncogenic role in promoting EMT. Although our and other studies have shown that FOXF2 dysregulation is critical for tumorigenesis of various tissue types, the role of FOXF2 in metabolic rewiring of cancer remains unknown. In this study, we analyzed our previous microarray data to understand the metabolic role of FOXF2 in non-cancerous and cancerous breast epithelial cells. Our studies showed that in non-cancerous breast epithelial cells FOXF2 can also play a dual role either in tumor suppression or in tumor promotion through regulating expression of tumor-suppressive and oncogenic metabolic genes. Furthermore, we found that FOXF2-regulated metabolic genes are not conserved between non-cancerous and cancerous breast epithelial cells and FOXF2 is involved in metabolic rewiring in breast cancer cells. This is the first report to explore the metabolic function of FOXF2 in breast cancer.

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“…To inhibit geranylgeranylation, cells were treated with the HMG CoA reductase inhibitor, lovastatin (LOV). To promote geranylgeranylation, cells in which the mevalonate pathway was inhibited with lovastatin were treated with the geranylgeranylation precursor, geranylgeraniol (GGOH), because GGOH can be converted to geranylgeranyl pyrophosphate and used for geranylgeranylation [30]. We assessed changes in outgrowth from cells cultured in serum containing medium (SCM, providing a source of cholesterol), serum-free medium (SFM, a condition known to induce outgrowth in B35 cells but not providing exogenous cholesterol), and SFM with the addition of a physiological concentration of synthetic cholesterol (SFM+Chol, Fig.…”

Section: Resultsmentioning

confidence: 99%

Inhibiting Geranylgeranylation Increases Neurite Branching and Differentially Activates Cofilin in Cell Bodies and Growth Cones

Samuel

Reddy²,

Kaimal³

et al. 2014

Mol Neurobiol

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Inhibitors of the mevalonate pathway, including the highly prescribed statins, reduce the production of cholesterol and isoprenoids such as geranylgeranyl pyrophosphates. The Rho family of small guanine triphosphatases (GTPases) requires isoprenylation, specifically geranylgeranylation, for activation. Because Rho GTPases are primary regulators of actin filament rearrangements required for process extension, neurite arborization and synaptic plasticity, statins may affect cognition or recovery from nervous system injury. Here, we assessed how manipulating geranylgeranylation affects neurite initiation, elongation and branching in neuroblastoma growth cones. Treatment with the statin, lovastatin (20 μM) decreased measures of neurite initiation by 17.0% to 19.0% when a source of cholesterol was present and increased neurite branching by 4.03 to 9.54 fold (regardless of exogenous cholesterol). Neurite elongation was increased by treatment with lovastatin only in cholesterol-free culture conditions. Treatment with lovastatin decreased growth cone actin filament content by up to 24.3%. In all cases, co-treatment with the prenylation precursor, geranylgeraniol (10 μM), reversed the effect of lovastatin. In prior work, statin effects on outgrowth were linked to modulating the actin depolymerizing factor, cofilin. In our assays, treatment with lovastatin or geranylgeraniol decreased cofilin phosphorylation in whole cell lysates. However, lovastatin increased cofilin phosphorylation in cell bodies and decreased it in growth cones, indicating differential regulation in specific cell regions. Together, we interpret these data to suggest that protein geranylgeranylation likely regulates growth cone actin filament content and subsequent neurite outgrowth through mechanisms that also affect actin nucleation and polymerization.

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Efficient Use of Exogenous Isoprenols for Protein Isoprenylation by MDA-MB-231 Cells Is Regulated Independently of the Mevalonate Pathway

Cited by 16 publications

References 25 publications

An obligatory role for neurotensin in high-fat-diet-induced obesity

An obligatory role for neurotensin in high-fat-diet-induced obesity

FOXF2 differentially regulates expression of metabolic genes in non-cancerous and cancerous breast epithelial cells

Inhibiting Geranylgeranylation Increases Neurite Branching and Differentially Activates Cofilin in Cell Bodies and Growth Cones

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