Growth control of lung cancer by interruption of 5-lipoxygenase-mediated growth factor signaling.
Signal transduction pathways shared by different autocrine growth factors may provide an efficient approach to accomplish clinically significant control of lung cancer growth. In this study, we demonstrate that two autocrine growth factors activate 5-lipoxygenase action of the arachidonic acid metabolic pathway in lung cancer cell lines. Both growth factors increased the production of 5(S)-hydrooxyeicosa-6E,8Z,11Z,14Z-tetraeno ic acid (5-HETE), a major early 5-lipoxygenase metabolic product. Exogenously added 5-HETE stimulated lung cancer cell growth in vitro. Inhibition of 5-lipoxygenase metabolism by selective antagonists resulted in significant growth reduction for a number of lung cancer cell lines. Primary clinical specimens and lung cancer cell lines express the message for the 5-lipoxygenase enzymes responsible for the generation of active metabolites. In vivo evaluation demonstrated that interruption of 5-lipoxygenase signaling resulted in enhanced levels of programmed cell death. These findings demonstrate that 5-lipoxygenase activation is involved with growth factor-mediated growth stimulation for lung cancer cell lines. Pharmacological intervention with lipoxygenase inhibitors may be an important new clinical strategy to regulate growth factor-dependent stages of lung carcinogenesis.
Avis
I M
IM
National Cancer Institute, Biomarkers and Prevention Research Branch, Rockville, Maryland 20850-3300, USA.
Jett
M
M
Boyle
T
T
Vos
M D
MD
Moody
T
T
Treston
A M
AM
Martínez
A
A
Mulshine
J L
JL
D058927:5-Lipoxygenase-Activating Proteins; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis* / Q000235:genetics; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism; D001483:Base Sequence; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000378:metabolism*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D019886:Gastrin-Releasing Peptide; D006133:Growth Substances / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D009637:Masoprocol / Q000627:therapeutic use; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D010455:Peptides / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D013002:Somatomedins / Q000494:pharmacology
D058927:5-Lipoxygenase-Activating Proteins; C548593:Alox5ap protein, mouse; D002352:Carrier Proteins; D006133:Growth Substances; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D010455:Peptides; D012333:RNA, Messenger; D013002:Somatomedins; D016718:Arachidonic Acid; D009637:Masoprocol; D019886:Gastrin-Releasing Peptide; D001094:Arachidonate 5-Lipoxygenase