BCAA metabolism: the Achilles' heel of ovarian cancer, polycystic ovary syndrome, and premature ovarian failure

Abstract

Branched-chain amino acids (BCAAs), including valine, leucine and isoleucine, are essential nutrient signals that influence mammalian animal metabolism. Many enzymes are involved in the metabolism of BCAAs, such as branched-chain amino acid transaminases (BCATs), branched-chain α-keto acid dehydrogenase (BCKDH), and BCKDH kinase (BCKDK). The aberrant expression of enzymes involved in BCAA metabolism and an imbalance in BCAA amino acid intake can lead to disordered metabolism. Aberrant BCAA metabolism can lead to several diseases, such as human ovarian disease, including ovarian cancer (OC), polycystic ovary syndrome (PCOS), and premature ovarian failure (POF), which are common gynaecological diseases. The overexpression of BCATs is found in OC, which promotes BCAA catalysis to provide a large amount of energy for tumorigenesis. However, BCKDK is overexpressed in epithelial ovarian cancer (EOC), which promotes proliferation and migration via MEK-ERK. In addition, several studies have reported that high levels of BCAAs are increased in the plasma of PCOS and POF patients. This review focuses on the role of BCAA metabolism and potential management methods for OC, PCOS and POF.

Keywords: branched-chain amino acids (BCAAs); human ovarian disease; metabolism; polycystic ovary syndrome (PCOS); premature ovarian failure (POF).

Figure 1

The molecular metabolic mechanisms of BCAAs. Valine, isoleucine and leucine are three types of BCAA, which are transformed into Kiv, Kic and Kmv, respectively, by the first key enzymes, BCATs. In this step, α-KG concurrently turns into glutamate. Moreover, Kiv, Kic and Kmv can be further decomposed into succinyl-CoA, acetyl-CoA and CO₂ by the BCKDH complex. The BCKDH complex is another key enzyme for BCAA metabolism and is inactivated by PPM1K and BCKDK. Succinyl-CoA and acetyl-CoA can enter the tricarboxylic acid cycle and break down into H₂O and CO₂.

Figure 2

High levels of BCAAs promote PCOS development and progression. BCAAs can be metabolized to 3-HIB to synthesize fatty acids, leading to obesity. The amount of BCAAs can increase the level of androgen by activating mTOR, which induces insulin synthesis and hyperinsulinaemia and insulin resistance. Hyperinsulin can activate the PI3K pathway to increase P450scc, CYP17A1 and StAR to drive the synthesis of hormones, including androgens. Furthermore, BCAAs can induce the upregulation of NF-kB and the production of ROS and H₂O₂, which can induce the occurrence, development and progression of atherosclerosis in PCOS patients by ICAM-1, E-selectin and HMGB1.

Figure 3

BCAAs drive POF development. BCAAs can competitively bind to LNAAs and be taken up by the brain across the blood–brain barrier. Hence, other amino acids (tyrosine, phenylalanine and tryptophan) accumulate in the brain, resulting in the upregulation of catecholamine and serotonin. High levels of catecholamines and serotonin increase the level of GnRH, which promotes the secretion of FSH and LH to induce the development and progression of POF.

Figure 4

The effect of BCAAs on ovarian cancer progression. Valine, isoleucine and leucine are transformed into BCKAs (Kiv, Kic and Kmv) via BCATs, which can be activated by c-Myc. However, the activity of BCKDH is decreased by high levels of PPM1K and BCKDK in ovarian cancer cells. High accumulation of BCKAs activates mTOR to promote ovarian cancer progression. BCKDK overexpression can also activate the MEK–ERK pathway to accelerate the progression of ovarian cancer. Leucine can interact with sestrin2 to competitively inhibit the binding of sestrin2 and GATOR2, resulting in GATOR2 interacting with mTOR to promote tumorigenesis. Moreover, high levels of BCAAs increase fatty acid synthesis to accelerate ovarian cancer development.