BCKDK of BCAA Catabolism Cross-talking With the MAPK Pathway Promotes Tumorigenesis of Colorectal Cancer
Peipei Xue,
Fanfan Zeng,
Qiuhong Duan,
Juanjuan Xiao,
Lin Liu,
Ping Yuan,
Linni Fan,
Huimin Sun,
Olesya S. Malyarenko,
Hui Lu,
Ruijuan Xiu,
Shaoqing Liu,
Chen Shao,
Jianmin Zhang,
Wei Yan,
Zhe Wang,
Jianyong Zheng,
Feng Zhu
Affiliations
Peipei Xue
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China
Fanfan Zeng
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China
Qiuhong Duan
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China
Juanjuan Xiao
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China
Lin Liu
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China
Ping Yuan
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China
Linni Fan
Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China
Huimin Sun
Department of Urology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China
Olesya S. Malyarenko
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China
Hui Lu
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China
Ruijuan Xiu
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China
Shaoqing Liu
Department of State Key Laboratory of Cancer Biology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China
Chen Shao
Department of Urology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China
Jianmin Zhang
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China
Wei Yan
Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China
Zhe Wang
Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China
Jianyong Zheng
Department of State Key Laboratory of Cancer Biology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China
Feng Zhu
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China
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.
