Expression of enzymes and receptors of the leukotriene pathway in human neuroblastoma promotes tumor survival and provides a target for therapy.
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 A(4) hydrolase, leukotriene C(4) 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 G(1)-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
Baldur
B
Childhood Cancer Research Unit, Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden. baldur.sveinbjornsson@ki.se
Rasmuson
Agnes
A
Baryawno
Ninib
N
Wan
Min
M
Pettersen
Ingvild
I
Ponthan
Frida
F
Orrego
Abiel
A
Haeggström
Jesper Z
JZ
Johnsen
John I
JI
Kogner
Per
P
D058927:5-Lipoxygenase-Activating Proteins; D017209:Apoptosis; D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000096:biosynthesis; D005982:Glutathione Transferase / Q000096:biosynthesis; D006801:Humans; D020024:Leukotriene Antagonists / Q000494:pharmacology; D015289:Leukotrienes / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D018077:Receptors, Leukotriene / Q000096:biosynthesis / Q000187:drug effects
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D018077:Receptors, Leukotriene; D001094:Arachidonate 5-Lipoxygenase; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases; C041116:leukotriene-C4 synthase; C043134:leukotriene A4 hydrolase