Department of Biochemistry and Molecular Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China.
Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
EBioMedicine. 2017 Jun;20:50-60. doi: 10.1016/j.ebiom.2017.05.001. Epub 2017 May 4.
Branched-chain amino acids catabolism plays an important role in human cancers. Colorectal cancer is the third most commonly diagnosed cancer in males and the second in females, and the new global incidence is over 1.2 million cases. The branched-chain α-keto acid dehydrogenase kinase (BCKDK) is a rate-limiting enzyme in branched-chain amino acids catabolism, which plays an important role in many serious human diseases. Here we investigated that abnormal branched-chain amino acids catabolism in colorectal cancer is a result of the disease process, with no role in disease initiation; BCKDK is widely expressed in colorectal cancer patients, and those patients that express higher levels of BCKDK have shorter survival times than those with lower levels; BCKDK promotes cell transformation or colorectal cancer ex vivo or in vivo. Mechanistically, BCKDK promotes colorectal cancer by enhancing the MAPK signaling pathway through direct MEK phosphorylation, rather than by branched-chain amino acids catabolism. And the process above could be inhibited by a BCKDK inhibitor, phenyl butyrate.
支链氨基酸代谢在人类癌症中起着重要作用。结直肠癌是男性中第三常见的癌症，在女性中排名第二，新的全球发病率超过 120 万例。支链α-酮酸脱氢酶激酶（BCKDK）是支链氨基酸代谢的限速酶，在许多严重的人类疾病中发挥着重要作用。在这里，我们研究了结直肠癌中异常的支链氨基酸代谢是疾病过程的结果，而不是疾病起始的原因；BCKDK在结直肠癌患者中广泛表达，并且表达较高水平 BCKDK 的患者的生存时间比表达较低水平 BCKDK 的患者短；BCKDK 促进细胞转化或结直肠癌细胞在体外或体内的生长。从机制上讲，BCKDK 通过直接磷酸化 MEK 增强 MAPK 信号通路来促进结直肠癌，而不是通过支链氨基酸代谢。上述过程可以被 BCKDK 抑制剂苯丁酸钠抑制。
