Pei Zhe, Lee Kuo-Chieh, Khan Amber, Wang Hoau-Yan
Department of Molecular, Cellular and Biomedical Sciences, City University of New York School of Medicine, 160 Convent Avenue, New York, NY 10031, USA.
Department of Molecular, Cellular and Biomedical Sciences, City University of New York School of Medicine, 160 Convent Avenue, New York, NY 10031, USA; Department of Biology, Neuroscience Program, Graduate School of The City University of New York, 365 Fifth Avenue, New York, NY 10061, USA.
Crit Rev Oncog. 2019;24(3):243-250. doi: 10.1615/CritRevOncog.2019031365.
Glioblastoma multiforme (GBM) is the most common and malignant glial tumor. Although pro-growth, pro-survival, and pro-metastasis insulin signaling has been proposed to be a prominent driver of GBM progression, the insulin receptor (IR) signaling cascade in GBM has not been fully elucidated. Upon binding of the insulin and insulin-like growth factor-1 (IGF-1), IR is activated by increasing the levels of tyrosine-phosphorylated (pY) IRP on tyrosine 960, 1150, and 1151 residues as well as IRS-1 recruitment to IRβ. This leads to activation of the downstream PI3K/AKT/GSK3 or mTORC1/ERK, many of which are implicated in tumorigenesis including breast and liver carcinomas. Here, we directly compare insulin signaling in U87 MG human glioblastoma to primary human astrocytes by assessing the levels of activated IRβ, IRS-1 recruitment to IRβ, as well as downstream activated mitogenic ERK2 and pro-survival AKT1 under nonstimulated conditions and induced by 1 nM insulin. Our results show insulin receptor and its downstream signaling molecules are robustly hyperactivated. This mechanism renders a reduced insulin-induced response. Our findings provide a mechanism through which GBM develops and grows aggressively even without insulin.
多形性胶质母细胞瘤（GBM）是最常见的恶性胶质肿瘤。尽管促生长、促存活和促转移的胰岛素信号已被认为是GBM进展的主要驱动因素，但GBM中的胰岛素受体（IR）信号级联尚未完全阐明。胰岛素和胰岛素样生长因子-1（IGF-1）结合后，IR通过增加酪氨酸960、1150和1151残基上酪氨酸磷酸化（pY）IRP的水平以及IRS-1募集到IRβ而被激活。这导致下游PI3K/AKT/GSK3或mTORC1/ERK的激活，其中许多与包括乳腺癌和肝癌在内的肿瘤发生有关。在这里，我们通过评估在非刺激条件下以及由1 nM胰岛素诱导的活化IRβ水平、IRS-1募集到IRβ的情况以及下游活化的有丝分裂原ERK2和促存活AKT1的水平，直接比较U87 MG人胶质母细胞瘤与原代人星形胶质细胞中的胰岛素信号。我们的结果表明胰岛素受体及其下游信号分子被强烈过度激活。这种机制导致胰岛素诱导的反应减弱。我们的发现提供了一种机制，通过该机制GBM即使在没有胰岛素的情况下也能积极发展和生长。
