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DOI: 10.1055/s-2004-824983
The Arginine Transporter ATB(0,+) is Upregulated in Colorectal Cancer
Introduction: Excess production of nitric oxide (NO) from arginine by the enzyme iNOS plays a crucial role in colorectal cancer. Recently, a highly efficient arginine transporter ATB0,+ has been described in human tissues. We hypothesize that ATB0,+ is upregulated in colorectal cancer as a means to deliver arginine to iNOS for excess NO production.
Methods: Total RNA was extracted from paired normal and cancer tissue harvested from colectomy specimens of 10 enrolled patients. Expression of ATB0,+ mRNA was determined by semi-quantitative RT-PCR and confirmed by Northern blot. ATB0,+ and iNOS protein expression was determined by immunohistochemistry (IHC). Excess NO was detected by IHC using antibodies against nitrosylated tyrosine residues.
Results: ATB0,+ mRNA showed an 11-fold increase in colorectal cancer by RT-PCR (the 95% lower confidence limit for relative expression was a 6.55 fold increase) and a greater than 10-fold increase by Northern blot. ATBO,+ protein expression showed a corresponding increase by IHC. ATB0,+ and iNOS proteins co-localized in the cell. Cancer tissue showed increased NO levels.
Conclusions: ATB0,+ is significantly up-regulated in colorectal cancer and co-localizes with iNOS. We propose that upregulation of ATB0,+ underlies production of NO in colorectal cancer. Since ATB0,+ has recently been shown to efficiently transport inhibitors of iNOS, this could provide a novel therapeutic strategy in colorectal cancer.