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

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.

Simultaneous silencing of β-catenin and signal transducer and activator of transcription 3 synergistically induces apoptosis and inhibits cell proliferation in HepG2 liver cancer cells

“…Similar to the present findings, in human squamous cell lung carcinomas, overexpression of the protein inhibitor of activated STAT3 promoted mitochondrial depolarization, leading to cytochrome C release, caspase-9 and caspase-3 activation, as well as PARP cleavage (22). In glioma cells (23), ovarian cancer cells (24), a urethane-induced lung tumor model (25), human renal cell carcinoma and melanoma cell lines (26), inhibition of STAT3 activity has been revealed to elevate the levels of cleaved caspase-3 and PARP, which is concordant with the results of the present study. In addition, β-catenin signaling is involved in the regulation of cell growth and apoptosis in breast cancer (27).…”

The Acute-Phase Protein Orosomucoid Regulates Food Intake and Energy Homeostasis via Leptin Receptor Signaling Pathway

“…As a member of the cytokine receptors, CCR5 activation also results in STAT3 phosphorylation in T cells (50). In addition, CCR5 deficiency suppressed lung tumor development through the inhibition of nuclear factor-kB/STAT3 pathways (51). Therefore, the remaining phosphorylation of STAT3 triggered by ORM might be the result of CCR5 signaling.…”

PRDX6 promotes tumor development via the JAK2/STAT3 pathway in a urethane-induced lung tumor model

“…Primary end-points of carcinogenesis were number, size, and histologic type of lung neoplastic lesions (atypical alveolar hyperplasia vs adenoma and adenocarcinoma). For C-C chemokine receptor (CCR) À / À and CCR þ / þ lung tumor tissues, we used equal samples as we previously reported [28].…”