Gupta Prakamya, Rai Ashutosh, Mukherjee Kanchan Kumar, Sachdeva Naresh, Radotra Bishan Das, Punia Raj Pal Singh, Vashista Rakesh Kumar, Hota Debasish, Srinivasan Anand, Dhandapani Sivashanmugam, Gupta Sunil Kumar, Bhansali Anil, Dutta Pinaki
Department of Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
Department of Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
Front Endocrinol (Lausanne). 2018 Aug 27;9:453. doi: 10.3389/fendo.2018.00453. eCollection 2018.
Imatinib, a tyrosine kinase inhibitor, causes growth failure in children with chronic myeloid leukemia probably by targeting the growth hormone (GH)/insulin like growth factor-1 (IGF-1) axis. We aim to explore the imatinib targets expression in pituitary adenomas and study the effect of imatinib on GH secretion in somatotropinoma cells and GH3 cell line. The expression pattern of imatinib's targets (c-kit, VEGF, and PDGFR-α/β) was studied using immunohistochemistry and immunoblotting 157 giant (≥4 cm) pituitary adenomas (121 non-functioning pituitary adenomas, 32 somatotropinomas, and four prolactinomas) and compared to normal pituitary ( = 4) obtained at autopsy. The effect imatinib on GH secretion, cell viability, immunohistochemistry, electron microscopy, and apoptosis was studied in primary culture of human somatotropinomas ( = 20) and in rat somato-mammotroph GH3 cell-line. A receptor tyrosine kinase array was applied to human samples to identify altered pathways. Somatotropinomas showed significantly higher immunopositivity for c-kit and platelet-derived growth factor receptor-β (PDGFR-β; < 0.009 and < 0.001, respectively), while staining for platelet-derived growth factor receptor-α (PDGFR-α) and vascular endothelial growth factor (VEGF) revealed a weaker expression ( < 0.001) compared to normal pituitary. Imatinib inhibited GH secretion from both primary culture ( < 0.01) and GH3 cells ( < 0.001), while it did not affect cell viability and apoptosis. The receptor tyrosine kinase array showed that imatinib inhibits GH signaling via PDGFR-β pathway. Imatinib inhibits GH secretion in somatotropinoma cells without affecting cell viability and may be used as an adjunct therapy for treating GH secreting pituitary adenomas.
伊马替尼是一种酪氨酸激酶抑制剂，可能通过靶向生长激素（GH）/胰岛素样生长因子-1（IGF-1）轴导致慢性髓性白血病儿童生长发育迟缓。我们旨在探究伊马替尼靶点在垂体腺瘤中的表达情况，并研究伊马替尼对生长激素瘤细胞和GH3细胞系中GH分泌的影响。采用免疫组织化学和免疫印迹法研究了157例巨大型（≥4 cm）垂体腺瘤（121例无功能性垂体腺瘤、32例生长激素瘤和4例催乳素瘤）中伊马替尼靶点（c-kit、血管内皮生长因子（VEGF）和血小板衍生生长因子受体-α/β（PDGFR-α/β））的表达模式，并与尸检获得的正常垂体组织（n = 4）进行比较。在人生长激素瘤原代培养物（n = 20）和大鼠生长激素-催乳素细胞GH3细胞系中研究了伊马替尼对GH分泌、细胞活力、免疫组织化学、电子显微镜检查和细胞凋亡的影响。应用受体酪氨酸激酶阵列对人样本进行检测以识别改变的信号通路。生长激素瘤中c-kit和血小板衍生生长因子受体-β（PDGFR-β）的免疫阳性率显著更高（分别为P < 0.009和P < 0.001），而与正常垂体相比，血小板衍生生长因子受体-α（PDGFR-α）和血管内皮生长因子（VEGF）的染色显示表达较弱（P < 0.001）。伊马替尼抑制原代培养物（P < 0.01）和GH3细胞（P < 0.001）中的GH分泌，但不影响细胞活力和细胞凋亡。受体酪氨酸激酶阵列显示伊马替尼通过PDGFR-β信号通路抑制GH信号传导。伊马替尼可抑制生长激素瘤细胞中的GH分泌而不影响细胞活力，可作为治疗分泌GH的垂体腺瘤的辅助治疗药物。
