Inhibition of chemerin/CMKLR1 axis in neuroblastoma cells reduces clonogenicity and cell viability in vitro and impairs tumor growth in vivo
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Conny Tümmler1, Igor Snapkov1, Malin Wickström2, Ugo Moens1, Linda Ljungblad2, Lotta Helena Maria Elfman2, Jan-Olof Winberg3, Per Kogner2, John Inge Johnsen2 and Baldur Sveinbjørnsson1,2
1Molecular Inflammation Research Group, Department of Medical Biology, Faculty of Health Science, University of Tromsø, Tromsø, Norway
2Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
3Tumor Biology Research Group, Department of Medical Biology, Faculty of Health Science, University of Tromsø, Tromsø, Norway
Conny Tümmler, email: [email protected]
Keywords: pediatric cancer, neuroblastoma, inflammation, GPCR, chemerin
Received: December 10, 2016 Accepted: July 06, 2017 Published: July 27, 2017
Pro-inflammatory cells, cytokines, and chemokines are essential in promoting a tumor supporting microenvironment. Chemerin is a chemotactic protein and a natural ligand for the receptors CMKLR1, GPR1, and CCRL2. The chemerin/CMKLR1 axis is involved in immunity and inflammation, and it has also been implicated in obesity and cancer.
In neuroblastoma, a childhood tumor of the peripheral nervous system we identified correlations between high CMKLR1 and GPR1 expression and reduced overall survival probability. CMKLR1, GPR1, and chemerin RNA and protein were detected in neuroblastoma cell lines and neuroblastoma primary tumor tissue. Chemerin induced calcium mobilization, increased MMP-2 synthesis as well as MAP-kinase- and Akt-mediated signaling in neuroblastoma cells. Stimulation of neuroblastoma cells with serum, TNFα or IL-1β increased chemerin secretion. The small molecule CMKLR1 antagonist α-NETA reduced the clonogenicity and viability of neuroblastoma cell lines indicating the chemerin/CMKLR1 axis as a promoting factor in neuroblastoma tumorigenesis. Furthermore, nude mice carrying neuroblastoma SK-N-AS cells as xenografts showed impaired tumor growth when treated daily with α-NETA from day 1 after tumor cell injection.
This study demonstrates the potential of the chemerin/CMKLR1 axis as a prognostic factor and possible therapeutic target in neuroblastoma.
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