Deficiency of C-C Chemokine Receptor 5 Suppresses Tumor Development via Inactivation of NF-κB and Upregulation of IL-1Ra in Melanoma Model

Ju Kyoung Song,Do Young Yoon,Hwan Soo Yoo,Sang Bae Han,Mi Hee Park,Dong-Young Choi,Jin Tae Hong,Jun Li

doi:10.1371/journal.pone.0033747

Ju Kyoung Song, Do Young Yoon + Show 6 more

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https://doi.org/10.1371/journal.pone.0033747

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Journal: PLoS ONE	Publication Date: May 2, 2012
Citations: 57	License type: CC BY 4.0

Affiliation: Konkuk University, Chungbuk National University

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.

Highlights

Chemokines are small soluble molecules that are best known for their potent ability to induce cancer cell growth by inflammation
The tumor growth in the CCR52/2 mice was reduced to 19.1%, whereas the tumor growth in the chemokine receptor type 5 (CCR5)+/+ mice was only reduced to 24.3%, in both tumor weight (Figure 1A and 1B) and tumor volume, respectively (Figure 1A and 1C)
We found that tumor weight and volume were much smaller in the CCR52/2 mice compared to the CCR5+/+ mice inoculated with B16 melanoma cells (Figure 1A and 1B)

Summary

Introduction

Chemokines are small soluble molecules that are best known for their potent ability to induce cancer cell growth by inflammation. The accumulated evidence indicates that the chemokine (C-C motif) ligand 5 (CCL5) and C-C chemokine receptor (CCR5), which are potent chemotactic factors for inflammatory cells, may be significantly involved in the proliferation and metastasis of several cancers. Host absence of CCR5 potentiates the delay of tumor growth [10], and CCR5 inhibitors prevented cancer cell growth, such as prostate cancer [11], breast cancer, hepatoma cells [4], and lung cancer [12]. These data suggest that the deficiency of inflammatory chemokine receptor CCR5 may function as a suppressive receptor in cancer progression. More studies are required to describe how CCR5 deficiency acts in the inhibition of tumor development

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