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Review
. 2018 Jan;21(1):64-70.
doi: 10.1097/MCO.0000000000000430.

Branched-chain amino acid metabolism in cancer

Elitsa A Ananieva  1 , Adam C Wilkinson
Affiliations
Review

Branched-chain amino acid metabolism in cancer

Elitsa A Ananieva et al. Curr Opin Clin Nutr Metab Care. 2018 Jan.

Abstract

Purpose of review: The current review aims to provide an update on the recent biomedical interest in oncogenic branched-chain amino acid (BCAA) metabolism, and discusses the advantages of using BCAAs and expression of BCAA-related enzymes in the treatment and diagnosis of cancers.

Recent findings: An accumulating body of evidence demonstrates that BCAAs are essential nutrients for cancer growth and are used by tumors in various biosynthetic pathways and as a source of energy. In addition, BCAA metabolic enzymes, such as the cytosolic branched-chain aminotransferase 1 (BCAT1) and mitochondrial branched-chain aminotransferase 2, have emerged as useful prognostic cancer markers. BCAT1 expression commonly correlates with more aggressive cancer growth and progression, and has attracted substantial scientific attention in the past few years. These studies have found the consequences of BCAT1 disruption to be heterogeneous; not all cancers share the same requirements for BCAA metabolites and the function of BCAT1 appears to vary between cancer types.

Summary: Both oncogenic mutations and cancer tissue-of-origin influence BCAA metabolism and expression of BCAA-associated metabolic enzymes. These new discoveries need to be taken into consideration during the development of new cancer therapies that target BCAA metabolism.

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Figures

FIGURE 1
FIGURE 1
A model of branched-chain amino acid metabolism in cancer. As essential amino acids, cancer cells must obtain branched-chain amino acids from the tumor microenvironment or from protein degradation. Branched-chain amino acids are thought to play several roles in cancer cells: activate complex 1 of the mammalian target of rapamycin signaling, which stimulates protein translation, growth, and survival; serve as building blocks in protein synthesis; be metabolized into branched-chain α-keto acids in the cytosol (by branched-chain aminotransferase 1) and/or mitochondria (by branched-chain aminotransferase 2), a process involving conversion of α-ketoglutarate to glutamate; serve as indirect source of nitrogen for nucleotide (and nonessential amino acid) biosynthesis via the glutamate–glutamine axis; and become further catabolized to yield acetyl-CoA and succinyl-CoA (not shown) that feed into the cycle of tricarboxylic acids cycle and can contribute to energy production. Note that in some cancers (such as chronic myeloid leukemia), branched-chain aminotransferase 1 is proposed to convert branched-chain α-keto acids back to branched-chain amino acids. BCAA, branched-chain amino acid; BCKA, branched-chain α-keto acid; BCKDH, branched-chain keto acid dehydrogenase; BC-acyl-CoAs, branched-chain acyl-CoAs; α-KG, α-ketoglutarate; TCA, cycle of tricarboxylic acids; mTORC1, complex 1 of the mammalian target of rapamycin.
Box 1
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