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

Carcinogenesis. 2012 Dec;33(12):2520-8. doi: 10.1093/carcin/bgs265. Epub 2012 Aug 20.

Abstract

To evaluate the significance of C-C 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 IĸB 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 growth-promoting 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • CCR5 Receptor Antagonists
  • CD8-Positive T-Lymphocytes / physiology
  • Chemokine CCL2 / antagonists & inhibitors*
  • Dendritic Cells / physiology
  • Disease Models, Animal
  • Humans
  • Lung Neoplasms / chemically induced
  • Lung Neoplasms / pathology
  • Lung Neoplasms / prevention & control*
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / physiology
  • Receptors, CCR5 / physiology*
  • STAT3 Transcription Factor / physiology
  • Urethane / toxicity

Substances

  • CCR5 Receptor Antagonists
  • Chemokine CCL2
  • NF-kappa B
  • Receptors, CCR5
  • STAT3 Transcription Factor
  • Urethane