Department of Health and Human Services, National Institutes of Health, National Cancer Institute, Center for Cancer Training, Bethesda, MD 20892, USA.
National Institute of Diabetes, Digestive and Kidney Disease, Digestive Diseases Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA.
Peptides. 2022 Oct;156:170858. doi: 10.1016/j.peptides.2022.170858. Epub 2022 Aug 3.
Neurotensin (NTS) receptor 1 regulates the growth non-small cell lung cancer (NSCLC) cells. NTS binds with high affinity to NTSR1, leading to increased tyrosine phosphorylation of the EGFR and HER2. Using Calu3, NCI-H358, or NCI-H441 cells, the effects of NTS on HER3 transactivation were investigated. HER3 tyrosine phosphorylation was increased by NTS or neuregulin (NRG1) addition to NSCLC cells. NCI-H358, NCI-H441, and Calu-3 cells have HER3, NTSR1 and neuregulin (NRG)1 protein. NTSR1 regulation of HER3 transactivation was impaired by SR48692 (NTSR1 antagonist) or monoclonal antibody (mAb)3481 (HER3 blocker). Immunoprecipitation experiments indicated that NTS addition to NCI-H441cells resulted in the formation of EGFR/HER3 and HER2/HER3 heterodimers. The ability of NTS to increase HER3 tyrosine phosphorylation was impaired by GM6001 (MMP inhibitor), PP2 (Src inhibitor), Tiron (superoxide scavenger), or N-acetylcysteine (antioxidant). Adding NTS to NSCLC cells increased phosphorylation of ERK, HER3, and AKT. NTS or NRG1 increased colony formation of NSCLC cells which was strongly inhibited by SR48692 and mAb3481. The results indicate that NTSR1 regulates HER3 transactivation in NSCLC cells leading to increased proliferation.
神经降压素（NTS）受体 1 调节非小细胞肺癌（NSCLC）细胞的生长。NTS 与 NTSR1 具有高亲和力结合，导致 EGFR 和 HER2 的酪氨酸磷酸化增加。使用 Calu3、NCI-H358 或 NCI-H441 细胞，研究了 NTS 对 HER3 转激活的影响。NTS 或神经调节蛋白（NRG1）的添加增加了 NSCLC 细胞中 HER3 的酪氨酸磷酸化。NCI-H358、NCI-H441 和 Calu-3 细胞具有 HER3、NTSR1 和神经调节蛋白（NRG）1 蛋白。NTSR1 对 HER3 转激活的调节被 SR48692（NTSR1 拮抗剂）或单克隆抗体（mAb）3481（HER3 阻滞剂）所损害。免疫沉淀实验表明，NTS 的添加导致 NCI-H441 细胞中 EGFR/HER3 和 HER2/HER3 异二聚体的形成。GM6001（基质金属蛋白酶抑制剂）、PP2（Src 抑制剂）、Tiron（超氧化物清除剂）或 N-乙酰半胱氨酸（抗氧化剂）可削弱 NTS 增加 HER3 酪氨酸磷酸化的能力。向 NSCLC 细胞中添加 NTS 增加了 ERK、HER3 和 AKT 的磷酸化。NTS 或 NRG1 增加了 NSCLC 细胞的集落形成，这一作用被 SR48692 和 mAb3481 强烈抑制。结果表明，NTSR1 调节 NSCLC 细胞中 HER3 的转激活，导致增殖增加。
