CCL11–CCR3 Interactions Promote Survival of Anaplastic Large Cell Lymphoma Cells via ERK1/2 Activation

Abstract

CCR3 is a specific marker of anaplastic large cell lymphoma (ALCL) cells. ALCL cells also express CCL11, a ligand for CCR3, leading to the hypothesis that CCL11 may play an autocrine role in ALCL progression. In this study, we investigated a role of CCL11 in cell survival and growth of human Ki-JK cells, established from an ALCL patient, and murine EL-4 lymphoma cells. Both Ki-JK and EL-4 cells expressed cell surface CCR3. CCL11 increased cell survival rates of Ki-JK cells in a dose-dependent manner, whereas it promoted EL-4 cell proliferation. Furthermore, CCL11 induced phosphorylation of extracellular signal-regulated kinase (ERK) 1/ 2 in both Ki-JK cells and EL-4 cells. Cell survival and tumor proliferation promoted by CCL11 was completely blocked by inhibition of ERK phosphorylation. CCL11 induced expression of antiapoptotic proteins, Bcl-xL and survivin, in Ki-JK cells. CCL11 also enhanced tumor growth of EL-4 and Ki-JK cells in vivo. Consistent with these results, tumor cells of cutaneous ALCL expressed CCR3 and increased levels of phosphorylated ERK1/2, Bcl-xL, and survivin in situ. Thus, our findings prompt a novel therapeutic approach to treat relapses of an aggressive form of lymphoma based on the discovery that a cell surface marker of disease functions as a critical autocrine growth receptor. Cancer Res; 71(6); 2056-65. Ó2011 AACR.

Expression and prognostic significance of CCL11/CCR3 in glioblastoma

“…Previous studies showed that the binding between CCL11 and CCR3 upregulated the expressions of VEGF, IL-8, PDGF-BB, and FGF [8–10]. In addition, it also induced phosphorylation of ERK1/2, MEK1 and STAT3 [5, 29]. Accordingly, CCL11 could act as: (1) an inflammatory chemokine contributing to the host response to neoplasia, (2) a proangiogenic factor promoting new vessel formation, (3) a general pro-inflammatory factor in response to tissue stress and/or necrosis, and/or (4) an autocrine growth factor released by cancer cells to promote proliferation, migration, and invasion [5, 8, 30].…”

“…It is widely expressed in human tissues including heart, colon, kidney, small intestine, lung, pancreas, liver, and ovary [3, 4]. CCL11 primarily binds to CCR3, a seven-transmembrane-domain G-protein-coupled chemokine receptor [5]. This binding triggers a series of signal transduction events involving transient release of intracellular calcium, cytoskeletal rearrangements, generation of inositol triphosphate, activation of protein kinase C and prolonged receptor internalization into an endocytic compartment [5–7].…”

“…CCL11 primarily binds to CCR3, a seven-transmembrane-domain G-protein-coupled chemokine receptor [5]. This binding triggers a series of signal transduction events involving transient release of intracellular calcium, cytoskeletal rearrangements, generation of inositol triphosphate, activation of protein kinase C and prolonged receptor internalization into an endocytic compartment [5–7]. In cancer, CCL11 and CCR3 facilitate proliferation, migration, and invasion of cancer cells [5, 8–13].…”

The Role of Chemoattractant Receptors in Shaping the Tumor Microenvironment

“…In anaplastic large cell lymphomas, the CCR3/CCL11 interaction promotes tumor cell proliferation and inhibits apoptosis through ERK1/2, Bcl-xL and the production of survivin [192]. Similarly, through an AKT signaling pathway, CCR7 and its ligands CCL19 and CCL21 induce squamous cell carcinoma of the head and neck growth in vitro and in vivo [230].…”

MiR‐92a mediates AZD6244 induced apoptosis and G1‐phase arrest of lymphoma cells by targeting Bim

“…After first-line chemotherapy, 15-20% of patients do not respond to its treatment; the short-and long-term toxicity of chemotherapy continues to adversely impacting the long-term prognosis of patients with lymphoma, making it important to explore strategies. Both T lymphoma and B lymphoma have active MEK/ERK (Chapuy et al, 2011;Miyagaki et al, 2011;Martin-Sanchez et al, 2013). Active ERK1/2 can phosphorylate a variety of substrates to promote cell proliferation, motility, and survival (Karin et al, 1997;Mebratu and Tesfaigzi, 2009;Roskoski, 2012;Courcelles et al, 2013).…”