SR48692 inhibits non-small cell lung cancer proliferation in an EGF receptor-dependent manner.
OBJECTIVE
The mechanism by which SR48692 inhibits non-small cell lung cancer (NSCLC) proliferation was investigated.


METHODS
The ability of SR48692 to inhibit the proliferation of NSCLC cell lines NCI-H1299 and A549 was investigated in vitro in the presence or absence of neurotensin (NTS). The ability of NTS to cause epidermal growth factor receptor (EGFR) transactivation was investigated by Western blot using NSCLC cells and various inhibitors. The growth effects and Western blot results were determined in cell lines treated with siRNA for NTSR1.


RESULTS
Treatment of A549 or NCI-H1299 cells with siRNA for NTSR1 reduced significantly NTSR1 protein and the ability of SR48692 to inhibit the proliferation of A549 or NCI-H1299 NSCLC cells. Treatment of A549 and NCI-H1299 cells with siRNA for NTSR1 reduced the ability of NTS to cause epidermal growth factor receptor (EGFR) transactivation. SR48692 or gefitinib (EGFR tyrosine kinase inhibitor) inhibited the ability of NTS to cause EGFR and ERK tyrosine phosphorylation. NTS transactivation of the EGFR was inhibited by GM6001 (matrix metalloprotease inhibitor), Tiron (superoxide scavenger) or U73122 (phospholipase C inhibitor) but not H89 (PKA inhibitor). NTS stimulates whereas SR48692 or gefitinib inhibits the clonal growth of NSCLC cells.


CONCLUSIONS
These results suggest that SR48692 may inhibit NSCLC proliferation in an EGFR-dependent mechanism.
Department of Health and Human Services, National Cancer Institute, Center for Cancer Research, Office of the Director, Bethesda, MD 20892, USA. Electronic address: moodyt@mail.nih.gov.
Terry W
TW
Moody
University of Colorado School of Medicine, Division of Medical Oncology, Aurora, CO 80045, USA.
Daniel C
DC
Chan
National Institute of Diabetes, Digestive and Kidney Disease, Digestive Diseases Branch, Bethesda, MD 20892, USA.
Samuel A
SA
Mantey
National Institute of Diabetes, Digestive and Kidney Disease, Digestive Diseases Branch, Bethesda, MD 20892, USA.
Paola
P
Moreno
National Institute of Diabetes, Digestive and Kidney Disease, Digestive Diseases Branch, Bethesda, MD 20892, USA.
Robert T
RT
Jensen
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases; D000077156:Gefitinib; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011720:Pyrazoles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D018028:Receptors, Neurotensin / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D016211:Transforming Growth Factor alpha / Q000502:physiology
D000970:Antineoplastic Agents; D011720:Pyrazoles; D011799:Quinazolines; D011804:Quinolines; D034741:RNA, Small Interfering; D018028:Receptors, Neurotensin; D016211:Transforming Growth Factor alpha; C114036:neurotensin type 1 receptor; C079087:SR 48692; C512478:EGFR protein, human; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D000077156:Gefitinib
Epidermal growth factor receptor; Lung cancer; Neurotensin; Transactivation; siRNA