SR48692 inhibits non-small cell lung cancer proliferation in an EGF receptor-dependent manner

Abstract

Aims The mechanism by which SR48692 inhibits non-small cell lung cancer (NSCLC) proliferation was investigated. Materials and Methods The ability of SR48692 to inhibit the proliferation of NSCLC cell lines NCI-H1299 and A549 were 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. Key findings 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. Significance These results suggest that SR48692 may inhibit NSCLC proliferation in an EGFR-dependent mechanism.

Targeting Neuropeptide Receptors for Cancer Imaging and Therapy: Perspectives with Bombesin, Neurotensin, and Neuropeptide-Y Receptors

“…NTSR 1 positivity was associated with lower survival rates (34). In vitro, neurotensin antagonist SR48692 inhibits proliferation (35). NTSR 1 is also expressed in 90% of mesotheliomas (36).…”

Neuropeptides as lung cancer growth factors

“…NTS activates the PI3K/Akt/mTOR pathway increasing cancer cellular survival [18]. NTS addition to NSCLC increases phosphorylation of the EGFR Tyr 1068 within minutes [42]. Fig.…”

“…Additional studies showed that if A549 NSCLC cells were treated with RNAi for NTS or NTSR1 and then implanted into nude mice, tumor growth was significantly slowed [1]. Treatment of NSCLC cells with RNAi for NTSR1, significantly impaired the ability of NTS to stimulate clonal growth and the ability of SR48692 to inhibit clonal growth [42].…”

NTSR1 (neurotensin receptor 1 (high affinity))

“…The recruitment of G protein was described through NTSR1 activation in microdomains (Heakal et al, 2011). In other cell types, cell proliferation, migration and invasion are depending on a transactivation of EGFR by NTSR1 (Amorino et al, 2007;Moody et al, 2014 ) or act through the increase of expression and activation of EGFR, HER2, HER3 (Younes et al, 2014;Dupouy et al, 2014).…”

“…Its activation enhances HER2, HER3 and EGFR expression in lung cancer (Younes et al, 2014). Pharmacological NTSR1 inhibitor (SR48692) inhibits EGFR activation (Moody et al, 2014).…”