Deficiency of C-C chemokine receptor 5 suppresses tumor development via inactivation of NF-kappa B and inhibition of monocyte chemoattractant protein-1 in urethane-induced lung tumor model

Title
Deficiency of C-C chemokine receptor 5 suppresses tumor development via inactivation of NF-kappa B and inhibition of monocyte chemoattractant protein-1 in urethane-induced lung tumor model
Author(s)
최동영이남진[이남진]송주경[송주경]정유연[정유연]김대환[김대환]김태명[김태명]김대중[김대중]권선미[권선미]김경보[김경보]최경은[최경은]문동철[문동철]김영수[김영수]한상배[한상배]홍진태[홍진태]
Keywords
COLONY-STIMULATING FACTOR; T-CELLS; SIGNALING PATHWAY; DENDRITIC CELLS; CANCER-THERAPY; DNA-BINDING; ACTIVATION; EXPRESSION; GROWTH; STAT3
Issue Date
201212
Publisher
OXFORD UNIV PRESS
Citation
CARCINOGENESIS, v.33, no.12, pp.2520 - 2528
Abstract
To evaluate the significance of CC chemokine receptor type 5 (CCR5) in lung tumor development, we compared carcinogen-induced tumor growth in CCR5 knockout (CCR5(/)) mice and wild-type (CCR5(/)) mice. CCR5(/) mice showed reduced urethane (1g/kg)-induced tumor incidence when compared with those of CCR5(/) mice. We investigated the activation of nuclear factor-kappaB/STAT3 since these are implicated transcription factors in the regulation of genes involving tumor growth. Significant inhibition of DNA-binding activity of nuclear factor-kappaB and STAT3, and the translocation of p50 and p65 into the nucleus and the phosphorylation of I?B were found in the lungs of CCR5(/) mice compared with the lungs of CCR5(/) mice. Expression of apoptotic protein such as cleaved caspase-3, cleaved PARP and Bax was elevated, whereas the expression levels of survival protein such as Bcl-2 and cIAP1 was decreased in the lungs of CCR5(/) mice. Interestingly, we found that the level of monocyte chemoattractant protein-1 (MCP-1), a tumor growthpromoting cytokine, was significantly reduced in the lung tumor tissue and blood of CCR5(/) mice compared with the level in CCR5(/) mice. In addition, CCR5 small interfering RNA (siRNA) and inhibitor of MCP-1 blocked lung cancer cell growth, which was abolished by the addition of MCP-1 protein in cultured lung cancer cells. Moreover, inactivation of CD8 cytotoxic T cell and dendritic cells was significantly increased in the blood, lung tumors and spleens of CCR5(/) mice compared with that of CCR5(/) mice. Therefore, these results showed that CCR5 deficiency suppressed lung tumor development through the inhibition of nuclear factor-kappaB/STAT3 pathways and the downregulation of MCP-1 in the carcinogen-induced lung tumor model.
URI
http://hdl.handle.net/YU.REPOSITORY/26874http://dx.doi.org/10.1093/carcin/bgs265
ISSN
0143-3334
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약학대학 > 약학부 > Articles
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