Abstract
Identifying bioenergetics that facilitate the epithelial to mesenchymal transition (EMT) in breast cancer cells may uncover targets to treat incurable metastatic disease. Metastasis is the number one cause of cancer-related deaths; therefore, it is urgent to identify new treatment strategies to prevent the initiation of metastasis. To characterize the bioenergetics of EMT, we compared metabolic activities and gene expression in cells induced to differentiate into the mesenchymal state with their epithelial counterparts. We found that levels of GLS2, which encodes a glutaminase, are inversely associated with EMT. GLS2 down-regulation was correlated with reduced mitochondrial activity and glutamine independence even in low-glucose conditions. Restoration of GLS2 expression in GLS2-negative breast cancer cells rescued mitochondrial activity, enhanced glutamine utilization, and inhibited stem-cell properties. Additionally, inhibition of expression of the transcription factor FOXC2, a critical regulator of EMT in GLS2-negative cells, restored GLS2 expression and glutamine utilization. Furthermore, in breast cancer patients, high GLS2 expression is associated with improved survival. These findings suggest that epithelial cancer cells rely on glutamine and that cells induced to undergo EMT become glutamine independent. Moreover, the inhibition of EMT leads to a GLS2-directed metabolic shift in mesenchymal cancer cells, which may make these cells susceptible to chemotherapies.
Highlights
Proliferative tumors consume glucose and amino acids, including glutamine, to sustain the metabolic demands that support biomass production [1]
To determine if the GLS2 and GLS inverse expression pattern we observed in the cell lines is evident in breast cancer patient samples, we compared GLS and GLS2 copy numbers in samples from 1075 patients using data from The Cancer Genome Atlas (TCGA)
When we compared amplifications and deletions of GLS2 among the PAM50 subtypes, we observed that the majority of the GLS2 copy number transcription factors Goosecoid (HMLE-GSC), Snail (HMLE-Snail), and Twist (HMLE-Twist) with deletions occurred in the mesenchymal stem cell-rich basal-like breast cancer subtype vector control (HMLE-V) cells
Summary
Proliferative tumors consume glucose and amino acids, including glutamine, to sustain the metabolic demands that support biomass production [1]. Glutaminolysis is the process whereby glutamine is converted to glutamate and to α-ketoglutarate, which enters the tricarboxylic acid (TCA) cycle. The TCA cycle supports oxidative phosphorylation and energy generation and provides a carbon source for fatty acid synthesis, a nitrogen source for synthesis of amino acids and nucleotides, and intermediates necessary for the synthesis of reduced glutathione (GSH), which neutralizes reactive oxygen species [2]. GLS and GLS2 have distinct patterns of expression and regulation in different organs and tumor types [3]. GLS is ubiquitously expressed and is highly expressed in several types of tumors as a result of direct regulation by oncogenes such as KRAS and MYC [4,5]. GLS2 is expressed mostly in the liver, brain, and pancreas and is directly regulated by p53, p63, and p73 [6,7,8]
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