Moody Terry W, Ramos-Alvarez Irene, Iordanskaia Tatiana, Mantey Samuel A, Jensen Robert T
Center for Cancer Training, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Digestive Disease Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Biology (Basel). 2025 Sep 9;14(9):1225. doi: 10.3390/biology14091225.
The bombesin (Bn) receptor family [Gastrin-releasing peptide (GRPR/BB2R) and Neuromedin B receptors (NMBR/BB1R)] are G-protein coupled receptors (GPCR's) with potent growth effects on normal tissues/numerous cancers, often by transactivating the ErbB receptor-tyrosine kinase (RTK) family. Whereas GRPR stimulation transactivates ErbB RTKs EGFR, HER2, and HER3 in non-small cell lung-cancer (NSCLC) cells, its effects on HER4 are unknown. This study was designed to address this question. Of 12 NSCLC's studied, 75% had HER4 mRNA expression and Western-Blotting. NCI-H522 and NCI-H661-cells had high levels of GRPR, HER4, and the HER4-ligand neuregulin (NRG1). Adding GRP to NCI-H522/NCI-H661-cells activated HER4, shown by its increased phosphorylation (P-HER4). The GRPR antagonists PD176252/BW2258U89 inhibited this increase. In NCI-H661-cells, GRP stimulated the formation of HER4-homodimers and HER2-HER4-heterodimers. Adding GRP to these NSCLC-cells increased P-ERK/P-AKT, which was inhibited by siRNA-HER4, PD176252, and ibrutinib, as well as -acetylcysteine and Tiron, which reduce reactive-oxygen species (ROS). GRP increased secretion of NRG1 from NSCLC-cells, and NRG1 increased P-HER4 and P-ERK, which were impaired by ibrutinib. GRP and NRG1 stimulated proliferation of NSCLC-cells, which was inhibited by PD176252, siRNA-HER4, or ibrutinib and which was mediated by MAPK, not AKT/PI3K, activation. These results show GRPR activation results in HER4 transactivation in a ROS-dependent manner, which stimulates NSCLC-growth through a MAPK-mediated mechanism.
胃泌素释放肽（Bn）受体家族[胃泌素释放肽受体（GRPR/BB2R）和神经介素B受体（NMBR/BB1R）]是G蛋白偶联受体（GPCR），对正常组织/多种癌症具有强大的生长作用，通常通过激活表皮生长因子受体（ErbB）受体酪氨酸激酶（RTK）家族来实现。虽然胃泌素释放肽受体（GRPR）刺激可激活非小细胞肺癌（NSCLC）细胞中的表皮生长因子受体（ErbB）受体酪氨酸激酶（RTK）家族成员表皮生长因子受体（EGFR）、人表皮生长因子受体2（HER2）和人表皮生长因子受体3（HER3），但其对人表皮生长因子受体4（HER4）的影响尚不清楚。本研究旨在解决这一问题。在研究的12例非小细胞肺癌中，75%有HER4信使核糖核酸（mRNA）表达和蛋白免疫印迹。NCI-H522和NCI-H661细胞中胃泌素释放肽受体（GRPR）、人表皮生长因子受体4（HER4）及HER4配体神经调节蛋白（NRG1）水平较高。向NCI-H522/NCI-H661细胞中添加胃泌素释放肽（GRP）可激活HER4，表现为其磷酸化增加（磷酸化HER4）。GRPR拮抗剂PD176252/BW2258U89可抑制这种增加。在NCI-H661细胞中，GRP刺激HER4同源二聚体和HER2-HER4异源二聚体的形成。向这些非小细胞肺癌细胞中添加GRP可增加磷酸化细胞外信号调节激酶（P-ERK）/磷酸化蛋白激酶B（P-AKT），而小干扰RNA（siRNA）-HER4、PD176252、伊布替尼以及可减少活性氧（ROS）的N-乙酰半胱氨酸和钛铁试剂可抑制这种增加。GRP可增加非小细胞肺癌细胞中NRG1的分泌，而NRG1可增加磷酸化HER4和磷酸化ERK，伊布替尼可损害这种作用。GRP和NRG1刺激非小细胞肺癌细胞增殖，PD176?252、siRNA-HER4或伊布替尼可抑制这种增殖，且这种增殖由丝裂原活化蛋白激酶（MAPK）而非蛋白激酶B（AKT）/磷脂酰肌醇-3激酶（PI3K）激活介导。这些结果表明，GRPR激活以ROS依赖的方式导致HER4反式激活，通过MAPK介导的机制刺激非小细胞肺癌生长。
