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Expression of enzymes and receptors of the leukotriene pathway in human neuroblastoma promotes tumor survival and provides a target for therapy

Baldur Sveinbjörnsson^*,,1,2, Agnes Rasmuson^*,1, Ninib Baryawno^*, Min Wan, Ingvild Pettersen, Frida Ponthan^*,||, Abiel Orrego, Jesper Z. Haeggström, John I. Johnsen^* and Per Kogner^*

^* Childhood Cancer Research Unit, Department of Woman and Child Health,

Department of Medical Biochemistry and Biophysics, and

Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden;

Department of Cell Biology and Histology, Faculty of Medicine, University of Tromsö, Tromsö, Norway; and

^|| Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK

²Correspondence: Childhood Cancer Research Unit, Astrid Lindgren Children’s Hospital, Q6:05, Karolinska Hospital, S-171 76 Stockholm, Sweden, E-mail: baldur.sveinbjornsson{at}ki.se

The metabolism of arachidonic acid by the cyclooxygenase (COX) or lipoxygenase (LO) pathways generates eicosanoids that have been implicated in the pathogenesis of a variety of human diseases, including cancer. In this study, we examined the expression and significance of components within the 5-LO pathway in human neuroblastoma, an embryonal tumor of the sympathetic nervous system. High expression of 5-LO, 5-LO-activating protein (FLAP), leukotriene A₄ hydrolase, leukotriene C₄ synthase, and leukotriene receptors was detected in a majority of primary neuroblastoma tumors and all cell lines investigated. Expression of 5-LO and FLAP was evident in tumor cells but not in nonmalignant adrenal medulla where neuroblastomas typically arise. Moreover, neuroblastoma cells produce leukotrienes, and stimulation of neuroblastoma cells with leukotrienes increased neuroblastoma cell viability. Inhibitors of 5-LO (AA-861), FLAP (MK-886), or the leukotriene receptor antagonist montelukast inhibited neuroblastoma cell growth by induction of G₁-cell cycle arrest and apoptosis. Similarly, specific 5-LO and leukotriene receptor silencing by small interfering RNA decreased neuroblastoma cell growth. These findings provide new insights into the pathobiology of neuroblastoma, and the use of leukotriene pathway inhibitors as a novel adjuvant therapy for children with neuroblastoma warrants further consideration.—Sveinbjörnsson, B., Rasmuson, A., Baryawno, N._, Wan, M., Ingvild Pettersen, I., Frida Ponthan, F., Orrego, A., Haeggström, J. Z., Johnsen, J. I., Kogner, P. Expression of enzymes and receptors of the leukotriene pathway in human neuroblastoma promotes tumor survival and provides a target for therapy.

Key Words: eicosanoids • 5-lipoxygenase • apoptosis