Deficiency of C-C chemokine receptor 5 suppresses tumor development via inactivation of NF-κB and upregulation of IL-1Ra in Melanoma model

Abstract

To evaluate the relevance of C-C chemokine receptor type 5 (CCR5) expression and tumor development, we compared melanoma growth in CCR5 knockout (CCR5-/-) mice and wild type (CCR5+/+) mice. CCR5-/- mice showed reduced tumor volume, tumor weight, and increased survival rate when compared to CCR5+/+ mice. We investigated the activation of NF-κB since it is an implicated transcription factor in the regulation of genes involving cell growth, apoptosis, and tumor growth. Significant inhibition of DNA binding activity of NF-κB, and translocation of p50 and p65 into the nucleus through the inhibition of phosphorylation of IκB was found in the melanoma tissues of CCR5-/- mice compared to melanoma tissues of CCR5+/+ mice. NF-κB target apoptotic protein expression, such as cleaved caspase-3, cleaved PARP, and Bax, was elevated, whereas the survival protein expression levels, such as Bcl-2, C-IAP1, was decreased in the melanoma tissues of CCR5-/- mice. Interestingly, we found that the level of IL-1Ra, a tumor growth suppressive cytokine, was significantly elevated in tumor tissue and spleen of CCR5-/- mice compared to the level in CCR5+/+ mice. Moreover, infiltration of CD8+ cytotoxic T cell and CD57+ natural killer cells was significantly increased in melanoma tumor and spleen tissue of CCR5-/- mice compared to that of CCR5+/+ mice. Therefore, these results showed that CCR5 deficiency caused apoptotic cell death of melanoma through inhibition of NF-κB and upregulation of IL-1Ra. © 2012 Song et al.