BCKDK of BCAA Catabolism Cross-talking With the MAPK Pathway Promotes Tumorigenesis of Colorectal Cancer

Autor: Chen Shao, Shaoqing Liu, Lin Liu, Ping Yuan, Zhe Wang, Jianmin Zhang, Feng Zhu, Huimin Sun, Fanfan Zeng, Ruijuan Xiu, Jianyong Zheng, Wei Yan, Qiuhong Duan, Juanjuan Xiao, Olesya S. Malyarenko, Hui Lu, Linni Fan, Peipei Xue
Rok vydání: 2017
Předmět:
Male
0301 basic medicine
Colorectal cancer
MAP Kinase Kinase 1
Gene Expression
lcsh:Medicine
BCKDHA
branched-chain α-keto acid dehydrogenase E1
medicine.disease_cause
Mice
0302 clinical medicine
ERK
extracellular signal-regulated kinase
BCKDK
branched-chain α-keto acid dehydrogenase kinase
Phosphorylation
Phenyl butyrate
lcsh:R5-920
Kinase
General Medicine
Prognosis
MEK
BCKA
branched- chain α-keto acid
Cell Transformation
Neoplastic
27HC
27-hydroxycholesterol
030220 oncology & carcinogenesis
CRC
colorectal cancer
Colorectal Neoplasms
lcsh:Medicine (General)
Research Paper
MAP Kinase Signaling System
BCKDK
Mouse model of colorectal and intestinal cancer
Biology
Phenylbutyrate
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
Cell Line
Tumor
PB
phenylbutyrate
medicine
Animals
Humans
Protein Kinase Inhibitors
Branched-chain amino acids catabolism
Catabolism
lcsh:R
Cancer
BCAA
branched-chain amino acids
medicine.disease
Molecular biology
Disease Models
Animal
030104 developmental biology
BCAT
branched- chain amino transferase
Tumorigenesis
Cancer research
Carcinogenesis
Protein Kinases
Amino Acids
Branched-Chain
MAPK
mitogen-activated protein kinase
Zdroj: EBioMedicine, Vol 20, Iss C, Pp 50-60 (2017)
EBioMedicine
ISSN: 2352-3964
DOI: 10.1016/j.ebiom.2017.05.001
Popis: 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.
Highlights • BCKDK, not BCAA promotes CRC tumorigenesis ex vivo or in vivo. • BCKDK phosphorylating MEK at Ser221. • BCKDK can be another valuable and potential biomarker for diagnosis of CRC. Colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the second in females. BCKDK is a key negative regulation enzyme in BCAA catabolism. Although BCAA catabolism is closely related with a variety of human cancers, the relationship between BCKDK and CRC is unclear. This study demonstrated a contribution of BCKDK promotes CRC tumorigenesis ex vivo or in vivo through directly phosphorylating MEK, rather than by increasing BCAA concentration. And BCKDK targeted inhibitors need to be designed and developed. This study suggested BCKDK can be another valuable and potential biomarker for diagnosis of CRC.
Databáze: OpenAIRE
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