Expression of 3-Methylcrotonyl-CoA Carboxylase in Brain Tumors and Capability to Catabolize Leucine by Human Neural Cancer Cells

Abstract

Leucine is an essential, ketogenic amino acid with proteinogenic, metabolic, and signaling roles. It is readily imported from the bloodstream into the brain parenchyma. Therefore, it could serve as a putative substrate that is complementing glucose for sustaining the metabolic needs of brain tumor cells. Here, we investigated the ability of cultured human cancer cells to metabolize leucine. Indeed, cancer cells dispose of leucine from their environment and enrich their media with the metabolite 2-oxoisocaproate. The enrichment of the culture media with a high level of leucine stimulated the production of 3-hydroxybutyrate. When 13C6-leucine was offered, it led to an increased appearance of the heavier citrate isotope with a molar mass greater by two units in the culture media. The expression of 3-methylcrotonyl-CoA carboxylase (MCC), an enzyme characteristic for the irreversible part of the leucine catabolic pathway, was detected in cultured cancer cells and human tumor samples by immunoprobing methods. Our results demonstrate that these cancer cells can catabolize leucine and furnish its carbon atoms into the tricarboxylic acid (TCA) cycle. Furthermore, the release of 3-hydroxybutyrate and citrate by cancer cells suggests their capability to exchange these metabolites with their milieu and the capability to participate in their metabolism. This indicates that leucine could be an additional substrate for cancer cell metabolism in the brain parenchyma. In this way, leucine could potentially contribute to the synthesis of metabolites such as lipids, which require the withdrawal of citrate from the TCA cycle.

Comparative Metabolomics Study of the Impact of Articaine and Lidocaine on the Metabolism of SH-SY5Y Neuronal Cells

“…Moreover, the BCKA resulting from those transamination reactions (KIC, KMV and KIV) can be oxidatively decarboxylated to produce acyl-CoA derivatives, which fuel the TCA cycle for energy production and/or lipid synthesis [ 50 ]. Indeed, Gondáš et al elegantly demonstrated that SH-SY5Y cells catabolized leucine into acetyl-CoA to supply the TCA cycle [ 51 ]. In this work, we show that ATC and LDC have a major impact on neuronal cells’ BCAA catabolism.…”

Discovery, Structure, and Function of Filamentous 3-Methylcrotonyl-CoA Carboxylase

“…3-methylcrotonyl-CoA carboxylase (MCC) is a biotin-dependent enzyme necessary for the catabolism of leucine (Anderson et al, 1998; Knappe et al, 1961; Nikolau et al, 2003), an essential branched-chain amino acid involved in regulating cellular metabolism (Gondáš et al, 2022; Yang et al, 2010), protein synthesis (Gondáš et al, 2022; Yang et al, 2010), and anabolic signaling (Gran and Cameron-Smith, 2011; Paulussen et al, 2021). MCC belongs to a superfamily of biotin-dependent carboxylases with different substrate preferences, such as acetyl-CoA carboxylase (ACC), geranyl-CoA carboxylase (GCC), propionyl-CoA carboxylase (PCC), and pyruvate carboxylase (PC).…”

“…Documented in many species (Diez et al, 1994; Gallardo et al, 2001; Höschle et al, 2005), MCC shares high cross-species sequence homology (Figure S1). In humans, upregulated MCC expression often correlates with various cancers (Chen et al, 2021; Dai et al, 2020; Gondáš et al, 2022; He et al, 2020; Liu et al, 2019). On the other hand, MCC deficiency, one of the most common metabolic disorders in newborns (Lee and Hong, 2014), may cause vomiting, seizures, and other neurological abnormalities (Grünert et al, 2012; Kim et al, 2017).…”

The Juggernaut of Adaptive Metabolism in Cancers: Implications and Therapeutic Targets

“…In their original article, Gondáš et al examined the unique ability of cultured human brain cancer cells (human glioma, glioblastoma, and neuroblastoma) to metabolize leucine (a ketogenic amino acid), an essential amino acid required for key cellular metabolic processes [ 11 ]. The authors reported that the enzyme 3-methylcrotonyl-CoA carboxylase (MCC), detected in the cultured cancer cells and human tumor samples, gave neoplastic tissue the ability to catabolize leucine and, thus, contribute to nitrogen metabolism in cancer cells and consequently utilize the derived carbon atoms in order to drive the Krebs/tri-carboxylic acid [ 11 ].…”

“…In their original article, Gondáš et al examined the unique ability of cultured human brain cancer cells (human glioma, glioblastoma, and neuroblastoma) to metabolize leucine (a ketogenic amino acid), an essential amino acid required for key cellular metabolic processes [ 11 ]. The authors reported that the enzyme 3-methylcrotonyl-CoA carboxylase (MCC), detected in the cultured cancer cells and human tumor samples, gave neoplastic tissue the ability to catabolize leucine and, thus, contribute to nitrogen metabolism in cancer cells and consequently utilize the derived carbon atoms in order to drive the Krebs/tri-carboxylic acid [ 11 ]. In fact, the 3-hydroxybutyrate and citrate produced by the cancer cells were efficiently exchanged for metabolites from the microenvironment, which were then utilized for their metabolic requirements, generating lipids and supporting energy metabolism, or they could be utilized as a building material within the cells’ anabolic processes, thus sustaining selective growth and proliferation [ 11 ].…”