Abstract
time RT-PCR of human colon tissue cDNAs showed higher expression of NK-1R in colon tumors than in normal colon. Western blot analyses showed that 3 of 5 different human colon tumor lysates express NK-1R while all matching adjacent normal colon tissues were negative for NK-1R. In NK-1R expressing human colonic cancer cells (transfected and nontransfected) SP induced ERK1/2 phosphorylation (Western blots), stimulated cell proliferation (MTS assay) via an ERK-1/2 dependent pathway, and inhibited cell apoptosis in response to Fas ligand (FasL). In modified Boyden chamber assays, SP augmented cell migration and invasiveness of SW620-NK-1R cells, indicating that SP may promote colon cancer development and metastasis. We next examined whether SP promotes colon cancer development In Vivo. Colitis was induced in colon cancer prone Apc/Min mice (n= 8 per group) by adding 5% dextran sulfate (DSS) in their drinking water for 5 days and then switched to drinking water for 8 week. Apc/Min mice were injected with the NK-1R antagonist CJ12255 5 mg/kg i.p. or vehicle every 2 d during the last two weeks of the experiment, then sacrificed and colon tumors were evaluated. ~80% of DSS-exposed mice in the vehicleinjected group showed an average of 4 colon tumors per mouse with tumor lyates showing elevated Akt and ERK1/2 phosphorylation. CJ-12225 treatment significantly reduced tumor onset, number and size, and inhibited Akt and ERK1/2 phosphorylation. DSS colitis (one week, 2% DSS) also promoted colon tumor formation after treatment with the carcinogen azoxymethane in wild-type mice. However, homozygous NK-1R knockout mice receiving the same treatment showed significantly less tumor onset, number and size. Conclusions: These are the first results indicating that SP and NK-1R participate in the development of colitis-associated colon cancer. Supported by a Research Fellowship from CCFA to HWK and a NIH grant DK47343 to CP.
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