Department of Health and Human Services, National Cancer Institute, Center for Cancer Research, Office of the Director, Bethesda, MD 20892, USA.
University of Colorado School of Medicine, Division of Medical Oncology, Aurora, CO 80045, USA.
Life Sci. 2014 Mar 28;100(1):25-34. doi: 10.1016/j.lfs.2014.01.072. Epub 2014 Feb 2.
The mechanism by which SR48692 inhibits non-small cell lung cancer (NSCLC) proliferation was investigated.
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.
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.
These results suggest that SR48692 may inhibit NSCLC proliferation in an EGFR-dependent mechanism.
研究 SR48692 抑制非小细胞肺癌（NSCLC）增殖的机制。
在存在或不存在神经降压素（NTS）的情况下，体外研究 SR48692 对 NSCLC 细胞系 NCI-H1299 和 A549 的增殖抑制能力。使用 NSCLC 细胞和各种抑制剂通过 Western blot 研究 NTS 引起表皮生长因子受体（EGFR）转激活的能力。用 NTSR1 的 siRNA 处理细胞系，确定生长效应和 Western blot 结果。
用 NTSR1 的 siRNA 处理 A549 或 NCI-H1299 细胞，显著降低了 NTSR1 蛋白和 SR48692 抑制 A549 或 NCI-H1299 NSCLC 细胞增殖的能力。用 NTSR1 的 siRNA 处理 A549 和 NCI-H1299 细胞，降低了 NTS 引起 EGFR 转激活的能力。SR48692 或吉非替尼（EGFR 酪氨酸激酶抑制剂）抑制了 NTS 引起的 EGFR 和 ERK 酪氨酸磷酸化。GM6001（基质金属蛋白酶抑制剂）、Tiron（超氧化物清除剂）或 U73122（PLC 抑制剂）但不是 H89（PKA 抑制剂）抑制了 NTS 对 EGFR 的转激活。NTS 刺激而 SR48692 或吉非替尼抑制 NSCLC 细胞的克隆生长。
这些结果表明，SR48692 可能通过 EGFR 依赖的机制抑制 NSCLC 增殖。
