title: 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.
authors.affiliation: Department of Dermatology, Faculty of Medicine, University of Tokyo, Japan.
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Miyagaki
authors.forename: Makoto
authors.initials: M
authors.lastname: Sugaya
authors.forename: Takashi
authors.initials: T
authors.lastname: Murakami
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Asano
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Tada
authors.forename: Takafumi
authors.initials: T
authors.lastname: Kadono
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okochi
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Tamaki
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sato
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054413:Chemokine CCL11 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004789:Enzyme Activation; D005260:Female; D015870:Gene Expression; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D054397:Receptors, CCR3 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D047368:Tumor Burden / Q000187:drug effects; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C107489:BIRC5 protein, human; D054413:Chemokine CCL11; D051034:Inhibitor of Apoptosis Proteins; D054397:Receptors, CCR3; D000077022:Survivin; D051020:bcl-X Protein; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3