Targeting Mitochondrial Citrate Transport in Breast Cancer Cell Lines

Ozkaya, Ali Burak; Ak, Handan; Atay, Sevcan; Aydin, Hikmet Hakan

doi:10.2174/1871520615666141216150659

Cited by 21 publications

(12 citation statements)

References 17 publications

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“…In a similar manner, the regulation of citrate transport may largely account the lack of significant changes in extracellular citrate. [ 37 ]. If citrate and pyruvate are not being actively transported across the membrane then any alteration in their production with the cell will not be reflected in the culture medium.…”

Section: Resultsmentioning

confidence: 99%

Suppression of PDHX by microRNA-27b deregulates cell metabolism and promotes growth in breast cancer

et al. 2018

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BackgroundThe disruption of normal gene regulation due to microRNA dysfunction is a common event in cancer pathogenesis. MicroRNA-27b is an example of an oncogenic miRNA, and it is frequently upregulated in breast cancer. MicroRNAs have been found to deregulate tumor metabolism, which typically manifests as heightened cellular glucose uptake in consort with increased flux through glycolysis, followed by the preferential conversion of glycolytic pyruvate into lactate (a phenomenon known as the Warburg Effect). Pyruvate Dehydrogenase, an enzyme complex linking glycolysis with downstream oxidative metabolism, represents a key location where regulation of metabolism occurs; PDHX is a key structural component of this complex and is essential for its function.MethodsWe sought to characterize the role of miR-27b in breast cancer by identifying novel transcripts under its control. We began by utilizing luciferase, RNA, and protein assays to establish PDHX as a novel target of miR-27b. We then tested whether miR-27b could alter metabolism using several metabolite assay kits and performed a seahorse analysis. We also examined how the altered metabolism might affect cell proliferation. Lastly, we confirmed the relevance of our findings in human breast tumor samples.ResultsOur data indicate that Pyruvate Dehydrogenase Protein X is a credible target of miR-27b in breast cancer. Mechanistically, by suppressing PDHX, miR-27b altered levels of pyruvate, lactate and citrate, as well as reducing mitochondrial oxidation and promoting extracellular acidification. These changes corresponded with an increased capacity for cell proliferation. In human breast tumor samples, PDHX expression was deficient, and low levels of PDHX were associated with reduced patient survival.ConclusionsMicroRNA-27b targets PDHX, resulting in an altered metabolic configuration that is better suited to fuel biosynthetic processes and cell proliferation, thereby promoting breast cancer progression.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0851-8) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Suppression of PDHX by microRNA-27b deregulates cell metabolism and promotes growth in breast cancer

et al. 2018

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“…The identified compound was also reported to inhibit both isoforms of ACC, making it impossible to rule out the role of off-target effects on the in vivo experimental outcomes. Interestingly, a competitive inhibitor of the mitochondrial citrate transport protein (CTP) fits this same structural class (Aluvila et al, 2010), and it was recently reported that this small molecule reduces cytoplasmic citrate levels in MCF-7 and MDA-MB-231 BC cells, reducing cell viability by 38.3% and 36.4%, respectively (Ozkaya et al, 2015).…”

Section: Targeting Dependence On Fa: Inhibiting Acly and Accmentioning

confidence: 99%

Fatty Acids and Breast Cancer: Make Them on Site or Have Them Delivered

Kinlaw

Baures

Lupien

et al. 2016

Journal Cellular Physiology

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Brisk fatty acid (FA) production by cancer cells is accommodated by the Warburg effect. Most breast and other cancer cell types are addicted to fatty acids (FA), which they require for membrane phospholipid synthesis, signaling purposes, and energy production. Expression of the enzymes required for FA synthesis is closely linked to each of the major classes of signaling molecules that stimulate BC cell proliferation. This review focuses on the regulation of FA synthesis in BC cells, and the impact of FA, or the lack thereof, on the tumor cell phenotype. Given growing awareness of the impact of dietary fat and obesity on BC biology, we will also examine the less-frequently considered notion that, in addition to de novo FA synthesis, the lipolytic uptake of preformed FA may also be an important mechanism of lipid acquisition. Indeed, it appears that cancer cells may exist at different points along a “lipogenic-lipolytic axis”, and FA uptake could thwart attempts to exploit the strict requirement for FA focused solely on inhibition of de novo FA synthesis. Strategies for clinically targeting FA metabolism will be discussed, and the current status of the medicinal chemistry in this area will be assessed.

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“…Several studies demonstrated that inhibition of CTP impaired LPS-induced activation of macrophages and DCs (Infantino et al, 2011;Everts et al, 2014). Because we found that 4-chloro-3-{[(3-nitrophenyl) amino]sulfonyl}benzoic acid, a CTP inhibitor (Ozkaya et al, 2015), slightly reduced LPS-induced expression of CD40 and CD86 in WT DCs (Figure 6A), we also considered that the increased citrate affected DC maturation in the cytosol. ATP citrate lyase (ACLY) is a cytosolic enzyme that converts citrate to oxaloacetate and acetyl-CoA, a key step for FAS.…”

Section: (Legend Continued On Next Page)mentioning

confidence: 99%