Conversion of Hyperpolarized [1-13C]Pyruvate in Breast Cancer Cells Depends on Their Malignancy, Metabolic Program and Nutrient Microenvironment

Abstract

Hyperpolarized magnetic resonance spectroscopy (MRS) is a technology for characterizing tumors in vivo based on their metabolic activities. The conversion rates (kpl) of hyperpolarized [1-13C]pyruvate to [1-13C]lactate depend on monocarboxylate transporters (MCT) and lactate dehydrogenase (LDH); these are also indicators of tumor malignancy. An unresolved issue is how glucose and glutamine availability in the tumor microenvironment affects metabolic characteristics of the cancer and how this relates to kpl-values. Two breast cancer cells of different malignancy (MCF-7, MDA-MB-231) were cultured in media containing defined combinations of low glucose (1 mM; 2.5 mM) and glutamine (0.1 mM; 1 mM) and analyzed for pyruvate uptake, intracellular metabolite levels, LDH and pyruvate kinase activities, and 13C6-glucose-derived metabolomics. The results show variability of kpl with the different glucose/glutamine conditions, congruent with glycolytic activity, but not with LDH activity or the Warburg effect; this suggests metabolic compartmentation. Remarkably, kpl-values were almost two-fold higher in MCF-7 than in the more malignant MDA-MB-231 cells, the latter showing a higher flux of 13C-glucose-derived pyruvate to the TCA-cycle metabolites 13C2-citrate and 13C3-malate, i.e., pyruvate decarboxylation and carboxylation, respectively. Thus, MRS with hyperpolarized [1-13C-pyruvate] is sensitive to both the metabolic program and the nutritional state of cancer cells.

Enhancing Cancer Diagnosis with Real-Time Feedback: Tumor Metabolism through Hyperpolarized 1-13C Pyruvate MRSI

“…In this paper, a lack of correlation of malignancy with LDH activities was reported. This is corroborated by studies with breast cancer xenografts in vivo [51] and cell lines in vitro [52]. Such a lack of correlation between pyruvate-to-lactate conversion and malignancy was also reported for hepatocellular carcinoma [53].…”

In Vitro Cell Death Mechanisms Induced by Dicoma anomala Root Extract in Combination with ZnPcS4 Mediated-Photodynamic Therapy in A549 Lung Cancer Cells

“…The mitochondria is also regarded as the powerhouse of the cell because its function is to synthesize energy molecules in the form of ATP [ 33 ]. The mitochondria also plays a significant role in metabolic pathways such as beta-oxidation, pyruvate decarboxylation, ketogenesis, and apoptosis initiation accomplished via ROS generation and apoptotic proteins activation [ 34 , 35 , 36 ].…”

Metabolic Reprogramming of Breast Tumor-Educated Macrophages Revealed by NMR Metabolomics

“…Exometabolomics further revealed that MDA-MB-231 cells, especially when cultured in hypoxia, and all macrophage subsets (M0 and TEM included) excrete citrate. Citrate secretion is a well-known feature of prostate epithelial cells [44] and astrocytes [45], where it is associated with specific physiological functions, but has seldom been reported for other cell types. Our observation that MDA-MB-231 cells, but not MCF-7 cells, secrete citrate may relate to the very recent findings by Grashei et al showing increased pyruvate influx into the TCA cycle in MDA-MB-231 cells compared to MCF-7 cells [45].…”

“…Citrate secretion is a well-known feature of prostate epithelial cells [44] and astrocytes [45], where it is associated with specific physiological functions, but has seldom been reported for other cell types. Our observation that MDA-MB-231 cells, but not MCF-7 cells, secrete citrate may relate to the very recent findings by Grashei et al showing increased pyruvate influx into the TCA cycle in MDA-MB-231 cells compared to MCF-7 cells [45]. Further, in that study, pyruvate-derived citrate was shown to partially originate from pyruvate carboxylation to oxaloacetate and reverse TCA cycle, which is in line with the high pyruvate carboxylase (PC) activity in BC tissues and MDA-MB-231 cells [46,47].…”