Multifaceted role of branched-chain amino acid metabolism in cancer

Abstract

Metabolic reprogramming fulfils increased nutrient demands and regulates numerous oncogenic processes in tumors, leading to tumor malignancy. Branched-chain amino acids (BCAAs, i.e., valine, leucine, and isoleucine) function as nitrogen donors to generate macromolecules such as nucleotides and are indispensable for human cancer cell growth. The cell-autonomous and non-autonomous roles of altered BCAA metabolism have been implicated in cancer progression and the key proteins in the BCAA metabolic pathway serve as possible prognostic and diagnostic biomarkers in human cancers. Here we summarize how BCAA metabolic reprogramming is regulated in cancer cells and how it influences cancer progression.

Inhibiting BCKDK in triple negative breast cancer suppress protein translation, impair mitochondrial function, and potentiate doxorubicin cytotoxicity

“…However, not only BCAA metabolites but also BCAA catabolizing enzymes have recently observed to influence cancer outcomes 11 . Indeed, upregulation of BCAT1 is reported in glioblastomas, HCC, leukemias, osteosarcomas, ovarian and endometrial cancer 27,29,11 . BCAT2 is upregulated in PDAC 25,26 , luminal type breast cancer 14 , NSCLC 28 , while it is downregulated in HCC 27 .…”

“…Indeed, degrading BCAAs and oxidizing BCKAs decreases cancer cell survival 10 . Although the role of BCKDH complex and BCAT isoforms (cytosolic BCAT1 or mitochondrial BCAT2) have been widely explored in different cancers 11 , the role of BCKDK remains mostly elusive. Recent studies have identified novel phosphorylation sites on BCKDK that stabilize BCKDK activity and influence tumor cell proliferation and survival 12,13 .…”

Transporters at the Interface between Cytosolic and Mitochondrial Amino Acid Metabolism

“…Aside from being used for protein synthesis, BCAAs can contribute to anabolic and bioenergetic outputs important for human physiology and dysregulated activity is attributed to multiple diseases (reviewed in [ 161 , 177 , 178 ]) ( Figure 4 ). Through catalytic activity of highly reversible branched chain aminotransferases (BCAT1/2) localized within the cytosol (BCAT1) or mitochondrial matrix (BCAT2), BCAA catabolism provides cells with amino-nitrogen for glutamate synthesis as well as branched chain ketoacids (BCKAs) (e.g., α-ketoisocaproic, KIC; α-ketoisovaleric, KIV; α-keto-β-methylvaleric, KMV) that contribute to acyl-CoA synthesis, lipogenesis, and TCA cycle metabolism.…”

“…BCKDH kinase (BCKDK) and the Mg 2+ /Mn 2+ -dependent 1 K protein phosphatase (PPM1K) coordinate the activity of BCKA oxidation. Activity of PPM1K was shown to positively regulate BCAA catabolism important for leukemogenesis [ 177 , 183 ]. Furthermore, defective BCKA oxidation drives the inborn error of metabolism maple syrup urine disease (MSUD), and dysregulated BCKDH activity is also attributed to several human diseases (e.g., diabetes, cancer) [ 184 ].…”

GEO data mining and TCGA analysis reveal altered branched chain amino acid metabolism in pancreatic cancer patients

“…Recent studies have highlighted the role of metabolic alteration in tumor development [ 1 , 2 ]. Branched chain amino acids (BCAAs), consisting of leucine, isoleucine and valine, are essential amino acids that can only be acquired from diet rather than de novo synthesized in human body.…”