title: Regulation of the metabolite profile by an APC gene mutation in colorectal cancer.
abstract: Mutation of the APC gene occurs during the early stages of colorectal cancer development. To obtain new insights into the mechanisms underlying the aberrant activation of the Wnt pathway that accompanies APC mutation, we carried out a gas chromatography-mass spectrometry-based semiquantitative metabolome analysis. In vitro experiments comparing SW480 cells expressing normal APC and truncated APC indicated that the levels of metabolites involved in the latter stages of the intracellular tricarboxylic acid cycle, including succinic acid, fumaric acid, and malic acid, were significantly higher in the SW480 cells expressing the truncated APC. In an in vivo study, we found that the levels of most amino acids were higher in the non-polyp tissues of APC(min/+) mice than in the normal tissues of the control mice and the polyp tissues of APC(min/+) mice. Ribitol, the levels of which were decreased in the polyp lesions of the APC(min/+) mice and the SW480 cells expressing the truncated APC, reduced the growth of SW480 cells with the APC mutation, but did not affect the growth of SW480 transfectants expressing full-length APC. The level of sarcosine was found to be significantly higher in the polyp tissues of APC(min/+) mice than in their non-polyp tissues and the normal tissues of the control mice, and the treatment of SW480 cells with 50 μM sarcosine resulted in a significant increase in their growth rate. These findings suggest that APC mutation causes changes in energetic metabolite pathways and that these alterations might be involved in the development of colorectal cancer.
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Yoshie
authors.forename: Shin
authors.initials: S
authors.lastname: Nishiumi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Izumi
authors.forename: Aya
authors.initials: A
authors.lastname: Sakai
authors.forename: Jun
authors.initials: J
authors.lastname: Inoue
authors.forename: Takeshi
authors.initials: T
authors.lastname: Azuma
authors.forename: Masaru
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002952:Citric Acid Cycle / Q000235:genetics / Q000502:physiology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005650:Fumarates / Q000032:analysis; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D006801:Humans; D008293:Malates / Q000032:analysis; D055432:Metabolomics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009154:Mutation; D012521:Sarcosine / Q000032:analysis; D019802:Succinic Acid / Q000032:analysis; D060449:Wnt Signaling Pathway
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D000596:Amino Acids; D005650:Fumarates; D008293:Malates; C030298:malic acid; C032005:fumaric acid; D019802:Succinic Acid; D012521:Sarcosine