OC is one of the most lethal cancers among women. As OC usually develops without well-defined clinical symptoms, it is diagnosed mostly in advanced stages with poor five-year survival rates of 15–45% 34. On the other hand, FIGO stage I OC is associated with a 90% or higher survival rate. To improve the diagnostic procedures and identify OC patients in early stages of the disease, various serum markers have been developed and used. CA125 was first reported as a tumor marker to detect ovarian tumors in the 1980s 35. However, the sensitivity and specificity of these markers are not high 36, 37. Therefore, the development of specific serum markers for screening without internal examinations is urgently needed, particularly for patients with ovarian cancer, who typically do not present any symptoms until an advanced stage. In addition, over the last 30 years, mortality rates from OC, including EOC, have slightly dropped 6, 38. The development of alternative synthetic lethal targets and diagnostic biomarkers is urgently needed.
The amino acid profile has been identified as an effective diagnostic tool in different cancers previously 39–42, and some amino acids are associated with OC 43–46, for example, leu 47. Branched-chain amino acid (BCAA) catabolism is closely related to tumors. The loss of BCAA catabolism promotes tumor development and growth 48, 49. The suppression of BCAA catabolic enzyme expression led to BCAA accumulation in tumors but not in regenerating liver tissues 48. Current research focuses on BCAT1 or BCAT2, which works in the first step of BCAA catabolism, while there are relatively few studies on BCKDK, which is a key negative regulatory enzyme in BCAA catabolism 50–53. Despite this, studies have shown that the overexpression of BCKDK promotes the growth and metastasis of various tumors 27–29. In this study, we determined that BCKDK promoted the proliferation and metastasis of EOC, and BCKDK was expressed at higher levels in EOC tissues than in adjacent normal tissues (Fig. 1b) and is correlated with advanced pathological grade for patients(Fig. 1e). This suggests that BCKDK could be another potential biomarker for the treatment of EOC. Inhibitors targeting BCKDK will be examined in future research.
Current research of BCAA catabolism worked in tumors focused on BCAT. As the BCAT reaction is reversible and near equilibrium, its direction should respond to changes in concentrations of BCAA and BCKAs, and availability of the donors and acceptors of nitrogen, to some extent, the conclusion was opposite in different researches. For example, some studies confirmed that the high expression of BCAT promoted the transfer of the BCAA amino group to α-ketoglutarate (α-KG) to form glutamate and the corresponding branched-chain keto acids (BCKAs). The BCAA catabolism was increasing, then the BCA-CoA entering into tricarboxylic acid cycle that provided energy for tumor cells proliferation and growth 53, 54. The other studies verified that the catabolism of BCAA in tumor cells was decreasing, and the high expression of BCAT promoted the conversion of BCKAs to BCAA and α-KG, and then providing essential nutrients and energy for cancer growth 48–49, 55. Our research supports the second. The overexpression of BCKDK inhibits the conversion of BCKAs to BCA-CoA, which leads to the accumulation of BCKAs. Furthermore, the accumulation of BCKAs inhibits BCAA catabolism. Therefore, BCKAs are converted into BCAAs again through amination with the BCAT enzyme. In addition, there are studies showing that BCKDK and PPM1K make up a ChREBP-regulated node that integrates BCAA and lipid metabolism and promotes BCAAs as a material for fat synthesis for fat cells, which provide energy for tumor growth 56. It has been proven that leu was increased in OC 47. Other studies also found that the overexpression of BCAT promoted OC proliferation 51–53. Therefore, our research gave a further understand of BCAA catabolism worked in the ovarian cancer. While, how BCKDK coordinated with BCAT to balance the BCAA metabolism? And whether they could directly regulate each other was still unclear.
Furthermore, to confirm the function of BCKDK in EOC, BCKDK was overexpressed in SKOV3 and OVCAR3 cells which poorly expressed BCKDK. BCKDK gain significantly promoted the proliferation and migration ex vivo, whereas knocked down the expression of BCKDK in HO8910-PM EOC cells reduced the proliferation and migration ex vivo and inhibited the tumor growth in vivo. Hence, these data supported the tumor-promoting function of BCKDK in EOC. These results were also consistent with previous findings demonstrating that BCKDK is a key regulator of cell proliferation and metastasis in colorectal cancer and hepatocellular carcinoma 27–29. Moreover, BCKDK promotes EOC proliferation and migration by activating the MEK/ERK signaling pathway. In agreement with our previous study, our previous study demonstrated that BCKDK promoted colorectal cancer proliferation by targetting the MEK1 27. Another previous study also verified that BCKDK promoted hepatocellular cancer proliferation by MEK/ERK signaling pathway 29. To our knowledge, this study was the first to report the ectopic expression of BCKDK in EOC, and uncovered the mechanism that BCKDK regulates EOC proliferation and migration by MEK/ERK signaling pathway.
Other studies also showed that BCKDK was closely related to lipid metabolism, which was upregulated by APN 55. In addition, BCKDK promoted tumor growth and metastasis by interacting with SRC or mTOR in colon cancer or hepatic carcinoma (Fig. 7) 28, 29. Therefore, in addition to the MEK-ERK pathway, whether the APN, SRC, or mTOR signaling pathways are also involved in this process still needs further examination. In addition, the drug resistance of ovarian cancer is a thorny issue, and and the mitochondria are closely related to apoptosis and autophagy-induced drug resistance 58–60. As BCKDK is located in the mitochondria, and related to drug resistance in ovarian cancer 30–31. What is the relevant mechanism? Many questions need to be addressed in the future. Due to the limited samples in this study, future studies need to expand the number of clinical samples and collect more clinical information.