CCR5/CCL5 axis interaction promotes migratory and invasiveness of pancreatic cancer cells

Abstract

Pancreatic cancer (PC) is one of the deadliest cancers and remains a major challenge due to its invasive and metastatic nature. Increased levels of CCR5 and CCL5 have established indicators for disease status in various cancers, including PC. However, their role in invasion and metastasis of PC is not known. Here we conducted immunohistochemistry of PC tissues and found elevated epithelial staining for CCR5 and CCL5 in metastatic PC tissues compared to non-neoplastic. In vitro experiments, such as flow cytometry, immunofluorescence and western blotting with human PC cell lines (AsPc-1, BxPc-3 and MIA PaCa-2), showed higher expression levels of CCR5. The CCL5 activation of PC cells expressing CCR5 increased their invasive potential, while treatment with CCR5 inhibitor maraviroc inhibited the CCL5 activation. CCL5 induced proliferation of PC cells was mediated through F-actin polymerization, while there was marked reduction when the cells were treated with maraviroc. The direct interaction of CCR5 with CCL5 was verified using a calcium mobilization assay. Taken together, our results demonstrate that CCR5 and CCL5 are potential markers for metastatic PC cancer, and their interaction leads to the increased PC cell invasion. Thus, blocking CCR5/CCL5 axis might prove beneficial to prevent metastasis and provide a more therapeutic strategy to control PC progression.

Reversal of drug resistance by planetary ball milled (PBM) nanoparticle loaded with resveratrol and docetaxel in prostate cancer

“…The method of RNA isolation was followed per our previous publication [18]. Briefly, Cells were treated for 48h with a known concentration of folic acid-conjugated nanoparticles as described above and lysed with Trizol reagent (Invitrogen, Paisley, UK) followed by the standard protocol for RNA extraction.…”

Biological and Clinical Significance of the CCR5/CCL5 Axis in Hepatocellular Carcinoma

“…These include evaluation of the CXCL12/CXCR4 axis in angiogenesis [15], the CCL20/CCR6 axis in the growth of the hepatoma cell line Huh7 [16]; and the CCL5/CCR1 axis in promoting the metastasis and invasion of HCC cells [17]. The chemokine ligand CCL5/RANTES (regulated upon activation, normal T-cell-expressed and secreted) promotes carcinogenesis and stroma genesis [18]. CCL5, a target gene of a nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [19], is expressed by various types of cells (T lymphocytes, macrophages, platelets, synovial fibroblasts, and tubular epithelium) [20].…”

“…CCL5 is secreted by certain types of tumor cells [21], and clinical studies show that elevated levels of CCL5 in tissues and plasma reflect adverse conditions for patients with melanoma, breast, cervical, prostate, gastric, or pancreatic cancer [22]. Although CCL5 binds to CCR1 and CCR3 receptors, the activity of CCL5 is expressed by binding to CCR5 [18].…”

miR-147a suppresses the metastasis of non-small-cell lung cancer by targeting CCL5

“…[21][22][23] Previous investigations have shown that CCL5 activates CCR5 to invoke a cascade of signaling pathways that increase the capacity of pancreatic cancer cells to invade or migrate to other organs. 24 It has been shown that miR-147a is downregulated in NSCLC cell lines and tissues. The aim of this study was to better understand the functions of miR-147a on the growth of NSCLC and to identify potential treatment targets for NSCLC.…”