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Background & Aims: Colorectal cancer(CRC)is the third most commonly diagnosed cancer in males and the second in females.The branched-chain a-keto acid dehydrogenase kinase(BCKDK)is a rate-limiting enzyme in the process of branched-chain amino acids(BCAA)catabolism.And many serious human diseases are caused by abnormal BCAA metabolism.Besides,BCKDK is highly expressed in colorectal tumor cell lines by the genome-scale sequencing analysis conducted by the Cancer Genome Atlas Network.Furthermore,the ratio of BCAT to BCKD in the entire gastrointestinal tract is high in primates.However,if BCKDK plays a crucial role in CRC is unclear.Here we investigated that BCKDK promotes colorectal cancer tumorigenesis via directly activating MEK1 at Ser221,and this process is inhibited by its inhibitors,phenylbutyrate and hydrocinnamic acid.Methods: Immunohistochemistry was used to analyze the level of BCKDK and BCKDHA(E1α)in human colorectal tumor tissue and corresponding tumor adjacent tissue.And survival time of CRC patients was also analyzed.After the plasmids of BCKDK and shBCKDK were stably or transiently transfected into different cell lines,these cell lines were used to analyze the abilities of colony formation and cell proliferation with EGF or inhibitors.Immunoprecipitation and IP kinase assay were used to analyze the interaction between BCKDK and MEK1.HCT116 cells with shBCKDK were grown as xenograft tumors in nude mice.Results: The level of BCKDK and BCKDHA are higher in human colorectal tumor tissue than corresponding tumor adjacent tissue.The survival time is shorter in the patients with high level of BCKDK.The number of colony formation dramaticlly increased in BCKDK stable cell lines.While,it is opposite in the shBCKDK cell lines or cells treated with BCKDK inhibitors.High concentration of BCAA couldnt promote JB6 Cl41 transformation in anchorage-independent cell transformation assay.BCKDK interacts with MEK1 and activates it by phosphorylating Ser 221 in vitro and in vivo.The tumor sizes in HCT116-shBCKDK group are smaller than HCT116 control group.Conclusions: Our findings define BCKDK promotes colorectal tumorigenesis by directly phosphorylating and activating MEK1 and it provides a promising diagnostic and therapeutic target for human CRCs.