The neuromedin U-growth hormone secretagogue receptor 1b/neurotensin receptor 1 oncogenic signaling pathway as a therapeutic target for lung cancer.
Using a genome-wide cDNA microarray to search for genes that were specifically up-regulated in non-small cell lung cancers (NSCLC), we identified an abundant expression of neuromedin U (NMU) in the great majority of lung cancers. Immunohistochemical analysis showed a significant association of NMU expression with poorer prognosis of patients with NSCLC. Treatment of NSCLC cells with short interfering RNA against NMU suppressed its expression and inhibited the growth of the cells; on the other hand, the induction of exogenous expression of NMU conferred growth-promoting activity and enhanced cell mobility in vitro. We found that two G protein-coupled receptors, growth hormone secretagogue receptor 1b and neurotensin receptor 1, were also overexpressed in NSCLC cells, and that a heterodimer complex of these receptors functioned as an NMU receptor. The NMU-receptor interaction subsequently induced the generation of a second messenger, cyclic AMP, to activate its downstream genes including transcription factors and cell cycle regulators. Treatment of NSCLC cells with short interfering RNAs for growth hormone secretagogue receptor or neurotensin receptor 1 suppressed the expression of those genes and the growth of NSCLC cells. These data strongly implied that targeting the NMU signaling pathway would be a promising therapeutic strategy for the treatment of lung cancers.
Takahashi
Koji
K
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Furukawa
Chiyuki
C
Takano
Atsushi
A
Ishikawa
Nobuhisa
N
Kato
Tatsuya
T
Hayama
Satoshi
S
Suzuki
Chie
C
Yasui
Wataru
W
Inai
Kouki
K
Sone
Saburo
S
Ito
Tomoo
T
Nishimura
Hitoshi
H
Tsuchiya
Eiju
E
Nakamura
Yusuke
Y
Daigo
Yataro
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019556:COS Cells; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D019281:Dimerization; D004705:Endocytosis; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000502:physiology*; D054440:Receptors, Ghrelin; D018028:Receptors, Neurotensin / Q000037:antagonists & inhibitors / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014162:Transfection
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D009479:Neuropeptides; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D018028:Receptors, Neurotensin; D011993:Recombinant Fusion Proteins; C114036:neurotensin type 1 receptor; C056900:neuromedin U; C046271:neuromedin U 25; D000242:Cyclic AMP