title: Upregulation of the amino acid transporter ATB0,+ (SLC6A14) in colorectal cancer and metastasis in humans.
abstract: ATB(0,+) (SLC6A14) is a Na(+)/Cl(-)-coupled arginine transporter expressed at low levels in normal colon. Arginine is an essential amino acid for tumor cells. Arginine is also the substrate for nitric oxide synthases (NOSs). Since arginine and arginine-derived nitric oxide (NO) play a critical role in cancer, we examined the expression of ATB(0,+) in colorectal cancer. Paired normal and cancer tissues from colectomy specimens of 10 patients with colorectal cancer and from the liver tissue of one patient with hepatic metastasis from a colonic primary were used for the analysis of the levels of ATB(0,+) mRNA, inducible NOS (iNOS) mRNA and the corresponding proteins. Tissues samples from the colon, liver, and lymph nodes of an additional patient with metastatic colon cancer were analyzed for ATB(0,+) protein alone. We also examined the levels of nitrotyrosylated proteins. The ATB(0,+) mRNA increased 22.9+/-3.0-fold in colorectal cancer compared to normal tissue and the increase was evident in each of the 10 cases examined. iNOS mRNA increased 5.2+/-1.1-fold in cancer specimens. The changes in mRNA levels were associated with an increase in ATB(0,+), iNOS, and nitrotyrosylated proteins. The increased expression of ATB(0,+) and iNOS was also demonstrated in liver and lymph node specimens with metastases from colonic primaries. This study strongly suggests that the upregulation of ATB(0,+) may have a pathogenic role in colorectal cancer. Since ATB(0,+) is a versatile transporter not only for arginine but also for several drugs including NOS inhibitors, these findings have significant clinical and therapeutic relevance.
authors.affiliation: Department of Surgery, Medical College of Georgia, Augusta, GA 30912-2100, USA.
authors.forename: Naren
authors.initials: N
authors.lastname: Gupta
authors.forename: Seiji
authors.initials: S
authors.lastname: Miyauchi
authors.forename: Robert G
authors.initials: RG
authors.lastname: Martindale
authors.forename: Anne V
authors.initials: AV
authors.lastname: Herdman
authors.forename: Robert
authors.initials: R
authors.lastname: Podolsky
authors.forename: Katsuya
authors.initials: K
authors.lastname: Miyake
authors.forename: Sela
authors.initials: S
authors.lastname: Mager
authors.forename: Puttur D
authors.initials: PD
authors.lastname: Prasad
authors.forename: Malliga E
authors.initials: ME
authors.lastname: Ganapathy
authors.forename: Vadivel
authors.initials: V
authors.lastname: Ganapathy
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D026923:Amino Acid Transport Systems, Basic; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000235:genetics; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D026923:Amino Acid Transport Systems, Basic; D012333:RNA, Messenger; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II