title: L-Leucine and L-isoleucine enhance growth of BBN-induced urothelial tumors in the rat bladder by modulating expression of amino acid transporters and tumorigenesis-associated genes.
abstract: We investigated the underlying mechanisms of L-leucine and L-isoleucine mediated promotion of bladder carcinogenesis using an initiation-promotion model. Rats were administered N-butyl-N-(4-hydroxybutyl) nitrosamine for 4 weeks and then fed AIN-93G basal diet or diet supplemented with L-leucine or L-isoleucine for 8 weeks followed by the basal diet for another 8 weeks. At the end of the experiment, week 20, there was a significant elevation of papillary and nodular (PN) hyperplasia multiplicity in the amino acid groups. L-Leucine and L-isoleucine transporters were up-regulated in PN hyperplasias and/or bladder tumors compared with concomitant normal-appearing bladder urothelium at weeks 12 and/or 20 in all groups. In addition, in normal-appearing bladder urothelium, significantly increased mRNA levels of y+LAT1, LAT2, LAT4, and 4F2hc were observed in the amino acid groups compared with the BBN control group at both weeks 12 and 20, and increased mRNA levels of LAT1 were observed at week 20. Furthermore, up-regulation of TNF-α, c-fos, β-catenin, p53, p21(Cip1/WAF1), cdk4, cyclin D1 and caspase 3 in the amino acid groups was detected in normal-appearing bladder urothelium. Overall, our results indicate that supplementation with l-leucine or l-isoleucine enhanced growth of bladder urothelial tumors by triggering expression of amino acid transporters and tumorigenesis-associated genes.
authors.affiliation: Department of Pathology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka, Japan.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Xie
authors.forename: Anna
authors.initials: A
authors.lastname: Kakehashi
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.forename: Shotaro
authors.initials: S
authors.lastname: Yamano
authors.forename: Masanori
authors.initials: M
authors.lastname: Takeshita
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yunoki
authors.forename: Hideki
authors.initials: H
authors.lastname: Wanibuchi
mesh_terms: D027182:Amino Acid Transport System y+ / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D026905:Amino Acid Transport Systems / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D026921:Amino Acid Transport Systems, Neutral / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000597:Amino Acids, Branched-Chain / Q000009:adverse effects* / Q000378:metabolism; D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced / Q000378:metabolism; D019587:Dietary Supplements / Q000009:adverse effects*; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D027301:Fusion Regulatory Protein 1, Light Chains / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006965:Hyperplasia; D007532:Isoleucine / Q000009:adverse effects / Q000378:metabolism; D027283:Large Neutral Amino Acid-Transporter 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007930:Leucine / Q000009:adverse effects / Q000378:metabolism; D008297:Male; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D047368:Tumor Burden; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D019459:Urothelium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: D027182:Amino Acid Transport System y+; D026905:Amino Acid Transport Systems; D026921:Amino Acid Transport Systems, Neutral; D000597:Amino Acids, Branched-Chain; D027282:Fusion Regulatory Protein 1, Heavy Chain; D027301:Fusion Regulatory Protein 1, Light Chains; D027283:Large Neutral Amino Acid-Transporter 1; D009363:Neoplasm Proteins; C486582:Slc7a8 protein, rat; D007532:Isoleucine; D007930:Leucine
keywords: Amino acid transporters; Tumorigenesis-associated genes; l-isoleucine; l-leucine