Targeting citrate as a novel therapeutic strategy in cancer treatment

Huang, Lan; Wang, Cindy; Xu, Huaxi; Peng, Guangyong

doi:10.1016/j.bbcan.2019.188332

Cited by 46 publications

(50 citation statements)

References 120 publications

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“…In support of the low citrate levels in MDA-MB-231 cells, citrate synthase expression and citrate synthase activity were both measured to be lower in MDA-MB-231 cells ( Figure 2 ). In additional support for citrate level in MDA-MB-231 cell line, it has been previously shown that more aggressive tumors present with lower steady state levels of citrate ( 36 , 37 ) and our findings confirm that understanding. We thereafter asked, that how can low citrate level justify central role of this metabolite in numerous cellular function that result in cancer cell homeostasis?…”

Section: Discussionsupporting

confidence: 89%

Metabolic and OXPHOS Activities Quantified by Temporal ex vivo Analysis Display Patient-Specific Metabolic Vulnerabilities in Human Breast Cancers

et al. 2020

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Research on mitochondrial metabolism and respiration are rapidly developing areas, however, efficient and widely accepted methods for studying these in solid tumors are still missing. Here, we developed a new method without isotope tracing to quantitate time dependent mitochondrial citrate efflux in cell lines and human breast cancer samples. In addition, we studied ADP-activated respiration in both of the sample types using selective permeabilization and showed that metabolic activity and respiration are not equally linked. Three times lower amount of mitochondria in scarcely respiring MDA-MB-231 cells convert pyruvate and glutamate into citrate efflux at 20% higher rate than highly respiring MCF-7 mitochondria do. Surprisingly, analysis of 59 human breast cancers revealed the opposite in clinical samples as aggressive breast cancer subtypes, in comparison to less aggressive subtypes, presented with both higher mitochondrial citrate efflux and higher respiration rate. Additionally, comparison of substrate preference (pyruvate or glutamate) for both mitochondrial citrate efflux and respiration in triple negative breast cancers revealed probable causes for high glutamine dependence in this subtype and reasons why some of these tumors are able to overcome glutaminase inhibition. Our research concludes that the two widely used breast cancer cell lines fail to replicate mitochondrial function as seen in respective human samples. And finally, the easy method described here, where time dependent small molecule metabolism and ADP-activated respiration in solid human cancers are analyzed together, can increase success of translational research and ultimately benefit patients with cancer.

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Section: Discussionsupporting

confidence: 89%

Metabolic and OXPHOS Activities Quantified by Temporal ex vivo Analysis Display Patient-Specific Metabolic Vulnerabilities in Human Breast Cancers

et al. 2020

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“…Once in the cytosol, citrate can be cleaved by ATP citrate lyase (ACLY) into acetyl-CoA and oxaloacetate. Acetyl-CoA is the substrate for various biochemical processes including fatty acid synthesis and histone acetylation for the epigenetic modifications of gene expression, 2 and oxaloacetate plays a key role in various biochemical processes including amino acid biosynthesis. As some of citrate’s many roles are associated with the mitochondrial pool, and others are associated with the cytoplasmic pool, methods that can enable the accurate determination of the concentration in both subcellular compartments are of high importance.…”

Section: Introductionmentioning

confidence: 99%

High-Performance Intensiometric Direct- and Inverse-Response Genetically Encoded Biosensors for Citrate

et al. 2020

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Motivated by the growing recognition of citrate as a central metabolite in a variety of biological processes associated with healthy and diseased cellular states, we have developed a series of high-performance genetically encoded citrate biosensors suitable for imaging of citrate concentrations in mammalian cells. The design of these biosensors was guided by structural studies of the citrate-responsive sensor histidine kinase and took advantage of the same conformational changes proposed to propagate from the binding domain to the catalytic domain. Following extensive engineering based on a combination of structure guided mutagenesis and directed evolution, we produced an inverse-response biosensor (Δ F / F min ≈ 18) designated Citroff1 and a direct-response biosensor (Δ F / F min ≈ 9) designated Citron1. We report the X-ray crystal structure of Citron1 and demonstrate the utility of both biosensors for qualitative and quantitative imaging of steady-state and pharmacologically perturbed citrate concentrations in live cells.

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“…Krebs cycle occurs in the mitochondria, however, several of its metabolites, including citrate, succinate, malate, oxaloacetate, fumarate, and α-ketoglutarate can be transported through the cell membrane by sodium-dependent SLC13 transporters (Markovich and Murer, 2004;Pajor, 2014). Citrate in particular gained a lot of interest, since its extracellular levels vary in diseases (Huang et al, 2020). Of particular interest is reported reduction in plasma citrate levels in prostate and lung cancers that readily metastasize to bone (Rocha et al, 2011;Dittrich et al, 2012), as well as in osteoporosis, in which citrate is also reduced in bone (major citrate reservoir) (Chen et al, 2018).…”

Section: Krebs Cycle Metabolitesmentioning

confidence: 99%

Role of Altered Metabolic Microenvironment in Osteolytic Metastasis

Tiedemann

Hussein

Komarova

2020

Front. Cell Dev. Biol.

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Metastatic bone disease is generally incurable and leads to pathological fractures, pain, hypercalcemia, spinal cord compression and decreased mobility. The skeleton is the major site of bone metastases from solid cancers, including breast and prostate carcinoma. Bone metastasis is facilitated by activation of bone-resorbing osteoclasts, terminally differentiated multinucleated cells formed by fusion from monocytic precursors. Cancer cells are known to produce specific factors that stimulate osteoclast differentiation and function. Of interest, cancer cells are also known to alter their own bioenergetics increasing the use of glycolysis for their survival and function. Such change in energy utilization by cancer cells would result in altered levels of cellpermeable metabolites, including glucose, lactate, and pyruvate. Osteoclast resorption is energy-expensive, and we have previously demonstrated that during differentiation osteoclasts actively adapt to their bioenergetics microenvironment. We hypothesize that altered bioenergetics state of cancer cells will also modify the bioenergetics substrate availability for the tissue-resident bone cells, potentially creating a favorable milieu for pathological osteolysis. The goals of this review are to analyze how metastasizing cancer cells change the availability of energy substrates in bone microenvironment; and to assess how the altered bioenergetics may affect osteoclast differentiation and activity.

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Targeting citrate as a novel therapeutic strategy in cancer treatment

Cited by 46 publications

References 120 publications

Metabolic and OXPHOS Activities Quantified by Temporal ex vivo Analysis Display Patient-Specific Metabolic Vulnerabilities in Human Breast Cancers

Metabolic and OXPHOS Activities Quantified by Temporal ex vivo Analysis Display Patient-Specific Metabolic Vulnerabilities in Human Breast Cancers

High-Performance Intensiometric Direct- and Inverse-Response Genetically Encoded Biosensors for Citrate

Role of Altered Metabolic Microenvironment in Osteolytic Metastasis

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