CCL5 and CCR5 Interaction Promotes Cell Motility in Human Osteosarcoma

Abstract

BackgroundOsteosarcoma is characterized by a high malignant and metastatic potential. CCL5 (previously called RANTES) was originally recognized as a product of activated T cells, and plays a crucial role in the migration and metastasis of human cancer cells. It has been reported that the effect of CCL5 is mediated via CCR receptors. However, the effect of CCL5 on migration activity and integrin expression in human osteosarcoma cells is mostly unknown.Methodology/Principal FindingsHere we found that CCL5 increased the migration and expression of αvβ3 integrin in human osteosarcoma cells. Stimulation of cells with CCL5 increased CCR5 but not CCR1 and CCR3 expression. CCR5 mAb, inhibitor, and siRNA reduced the CCL5-enhanced the migration and integrin up-regulation of osteosarcoma cells. Activations of MEK, ERK, and NF-κB pathways after CCL5 treatment were demonstrated, and CCL5-induced expression of integrin and migration activity was inhibited by the specific inhibitor and mutant of MEK, ERK, and NF-κB cascades. In addition, over-expression of CCL5 shRNA inhibited the migratory ability and integrin expression in osteosarcoma cells.Conclusions/SignificanceCCL5 and CCR5 interaction acts through MEK, ERK, which in turn activates NF-κB, resulting in the activations of αvβ3 integrin and contributing the migration of human osteosarcoma cells.

Cisplatin-induced CCL5 secretion from CAFs promotes cisplatin-resistance in ovarian cancer via regulation of the STAT3 and PI3K/Akt signaling pathways

“…Based on these reports, we examined the signaling pathways activated by CCL5 in vitro and in vivo and found that STAT3 phosphorylation was enhanced in a time-and dose-dependent manner. We also found that AKT phosphorylation levels, which play a vital role in tumor malignancy phenotype, were significantly activated by CCL5 stimulation, consistent with previous reports (19,33,34). Next, we used small molecular interfering RNA to knock down STAT3 gene expression or the small molecular inhibitor LY294002 to inhibit the PI3K-Akt signaling pathway.…”

“…The PI3K/Akt signaling pathway plays a vital role in the regulation of numerous cellular functions, including tumor progression, angiogenesis, adhesion, migration, survival and drug resistance, in many human cancers (31) and is involved in cisplatin-based chemotherapy resistance in epithelial ovarian cancer (32). In addition, the Akt signaling pathway can be activated via chemokines or cytokines, such as CCL5 (19,33,34). We hypothesized that these two pathways were involved in the regulation of cisplatin resistance by CCL5.…”

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

“…CCL5 also induces migration by upregulating the activities of MMP-9 through STAT3 [55]. CCL5 mediates diverse physiological responses through its receptor, CCR5, and thus signaling based on interactions between CCL5 and CCR5 also leads to increased cell proliferation [56,57]. In the present study, we found that CCL5 was upregulated in the tumor lung tissues of PRDX6-Tg mice and it activated the JAK2/STAT3 pathway, whereas the deficiency of its receptor CCR5 (CCR5 À / À mice) resulted in the reduction of JAK2 activities in urethane-induced lung tumor tissues.…”

Tunicamycin-induced ER stress regulates chemokine CCL5 expression and secretion via STAT3 followed by decreased transmigration of MCF-7 breast cancer cells

“…The results revealed that although ER stress upregulated intracellular CCL5 expression, it inhibited CCL5 secretion of MCF-7 cells. According to studies of Wang et al (10) and Lin et al (28), CCL5 promotes tumour cell motility and migration by interacting with a specific receptor chemokine C-C motif receptor 5 (CCR5). Thus, we assume that it is the extracellular CCL5 in the microenvironment of tumour cells that actually stimulates the migration, while the intracellular expression level of CCL5 does not affect the migration ability of cancer cells directly.…”

“…Expression of CCL5 is upregulated in breast cancer, and is correlated to disease progression (7,8). Elevated CCL5 in tumours promotes cell motility, migration, invasion and metastasis (9,10) and inhibition of tumour-derived CCL5 attenuates the metastasis of tumours (11).…”