Probing the metabolic phenotype of breast cancer cells by multiple tracer stable isotope resolved metabolomics

Lane, Andrew N.; Tan, Julie; Wang, Yali; Yan, Jun; Higashi, Richard M.; Fan, Teresa W.‐M.

doi:10.1016/j.ymben.2017.01.010

Cited by 51 publications

(47 citation statements)

References 65 publications

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“…In accordance with our results, the GPAT2 expression was found to be much higher in MDA-MB-231 than in the HeLa and MCF7 cells lines, which present a low GPAT2 expression [39]. Indeed, glucose was seen to be incorporated into glycerol and fatty acyl chains in breast epithelial cells (HMEC), and breast tumor cell lines MCF7 and ZR75-1, but only to glycerol in MDA-MB-231 cells [42]. However, in that article, the effect of glucose on FA uptake was not studied [42].…”

Section: Discussionsupporting

confidence: 90%

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Glucose Favors Lipid Anabolic Metabolism in the Invasive Breast Cancer Cell Line MDA-MB-231

Ocaña

Martínez‐Poveda

Quesada

et al. 2020

Biology

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Metabolic reprogramming in tumor cells is considered one of the hallmarks of cancer. Many studies have been carried out in order to elucidate the effects of tumor cell metabolism on invasion and tumor progression. However, little is known about the immediate substrate preference in tumor cells. In this work, we wanted to study this short-time preference using the highly invasive, hormone independent breast cancer cell line MDA-MB-231. By means of Seahorse and uptake experiments, our results point to a preference for glucose. However, although both glucose and glutamine are required for tumor cell proliferation, MDA-MB-231 cells can survive two days in the absence of glucose, but not in the absence of glutamine. On the other hand, the presence of glucose increased palmitate uptake in this cell line, which accumulates in the cytosol instead of going to the plasma membrane. In order to exert this effect, glucose needs to be converted to glycerol-3 phosphate, leading to palmitate metabolism through lipid synthesis, most likely to the synthesis of triacylglycerides. The effect of glucose on the palmitate uptake was also found in other triple-negative, invasive breast cancer cell lines, but not in the non-invasive ones. The results presented in this work suggest an important and specific role of glucose in lipid biosynthesis in triple-negative breast cancer.

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Section: Discussionsupporting

confidence: 90%

“…Indeed, glucose was seen to be incorporated into glycerol and fatty acyl chains in breast epithelial cells (HMEC), and breast tumor cell lines MCF7 and ZR75-1, but only to glycerol in MDA-MB-231 cells [42]. However, in that article, the effect of glucose on FA uptake was not studied [42].…”

Section: Discussionmentioning

confidence: 93%

Glucose Favors Lipid Anabolic Metabolism in the Invasive Breast Cancer Cell Line MDA-MB-231

Ocaña

Martínez‐Poveda

Quesada

et al. 2020

Biology

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“…The EC-MS analysis was carried out by Human Metabolome Technologies (HMT) 55 , 56 . The NMR analysis was carried out at the Oregon State University NMR core facility 57 , 58 . With both analyses, levels of 13 C-labelled glucose metabolites were adjusted by viable cell numbers, and expressed as % relative to R1881/20% O 2 .…”

Section: Methodsmentioning

confidence: 99%

Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted therapy

et al. 2018

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Despite recent advances, the efficacy of androgen/androgen receptor (AR)-targeted therapy remains limited for many patients with metastatic prostate cancer. This is in part because prostate cancers adaptively switch to the androgen/AR-independent pathway for survival and growth, thereby conferring therapy resistance. Tumor hypoxia is considered as a major cause of treatment resistance. However, the exact mechanism is largely unclear. Here we report that chronic-androgen deprivation therapy (ADT) in the condition of hypoxia induces adaptive androgen/AR-independence, and therefore confers resistance to androgen/AR-targeted therapy, e.g., enzalutamide. Mechanistically, this is mediated by glucose-6-phosphate isomerase (GPI), which is transcriptionally repressed by AR in hypoxia, but restored and increased by AR inhibition. In turn, GPI maintains glucose metabolism and energy homeostasis in hypoxia by redirecting the glucose flux from androgen/AR-dependent pentose phosphate pathway (PPP) to hypoxia-induced glycolysis pathway, thereby reducing the growth inhibitory effect of enzalutamide. Inhibiting GPI overcomes the therapy resistance in hypoxia in vitro and increases enzalutamide efficacy in vivo.

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“…Spheroids are formed reproducibly within minutes to hours in cell repellent plates and are biocompatible for various functional assays including toxicity testing [ 1 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. This matrix-free method is particularly amenable for Stable Isotope-Resolved Metabolomic (SIRM) studies [ 2 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ] as securing spheroids with magnets enables rapid tracer medium change, sampling at different time points or removal during metabolic quenching. Here, we demonstrate the utility of coupling the M3DB culturing with SIRM in exploring the metabolic mechanism that underlies the increased resistance to anti-cancer sodium selenite in 3D spheroids formed from lung (A549) and pancreatic (PANC1) adenocarcinoma cells versus their 2D cell counterparts.…”

Section: Introductionmentioning

confidence: 99%

Stable Isotope-Resolved Metabolomics Shows Metabolic Resistance to Anti-Cancer Selenite in 3D Spheroids versus 2D Cell Cultures

et al. 2018

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Conventional two-dimensional (2D) cell cultures are grown on rigid plastic substrates with unrealistic concentration gradients of O2, nutrients, and treatment agents. More importantly, 2D cultures lack cell–cell and cell–extracellular matrix (ECM) interactions, which are critical for regulating cell behavior and functions. There are several three-dimensional (3D) cell culture systems such as Matrigel, hydrogels, micropatterned plates, and hanging drop that overcome these drawbacks but they suffer from technical challenges including long spheroid formation times, difficult handling for high throughput assays, and/or matrix contamination for metabolic studies. Magnetic 3D bioprinting (M3DB) can circumvent these issues by utilizing nanoparticles that enable spheroid formation and growth via magnetizing cells. M3DB spheroids have been shown to emulate tissue and tumor microenvironments while exhibiting higher resistance to toxic agents than their 2D counterparts. It is, however, unclear if and how such 3D systems impact cellular metabolic networks, which may determine altered toxic responses in cells. We employed a Stable Isotope-Resolved Metabolomics (SIRM) approach with 13C6-glucose as tracer to map central metabolic networks both in 2D cells and M3DB spheroids formed from lung (A549) and pancreatic (PANC1) adenocarcinoma cells without or with an anti-cancer agent (sodium selenite). We found that the extent of 13C-label incorporation into metabolites of glycolysis, the Krebs cycle, the pentose phosphate pathway, and purine/pyrimidine nucleotide synthesis was largely comparable between 2D and M3DB culture systems for both cell lines. The exceptions were the reduced capacity for de novo synthesis of pyrimidine and sugar nucleotides in M3DB than 2D cultures of A549 and PANC1 cells as well as the presence of gluconeogenic activity in M3DB spheroids of PANC1 cells but not in the 2D counterpart. More strikingly, selenite induced much less perturbation of these pathways in the spheroids relative to the 2D counterparts in both cell lines, which is consistent with the corresponding lesser effects on morphology and growth. Thus, the increased resistance of cancer cell spheroids to selenite may be linked to the reduced capacity of selenite to perturb these metabolic pathways necessary for growth and survival.

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Probing the metabolic phenotype of breast cancer cells by multiple tracer stable isotope resolved metabolomics

Cited by 51 publications

References 65 publications

Glucose Favors Lipid Anabolic Metabolism in the Invasive Breast Cancer Cell Line MDA-MB-231

Glucose Favors Lipid Anabolic Metabolism in the Invasive Breast Cancer Cell Line MDA-MB-231

Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted therapy

Stable Isotope-Resolved Metabolomics Shows Metabolic Resistance to Anti-Cancer Selenite in 3D Spheroids versus 2D Cell Cultures

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