Loss of G-Protein Pathway Suppressor 2 Promotes Tumor Growth Through Activation of AKT Signaling.
Loss of G-Protein Pathway Suppressor 2 Promotes Tumor Growth Through Activation of AKT Signaling.
复制标题
DOI：
10.3389/fcell.2020.608044
复制
发表时间：
2020
影响因子：
5.5
通讯作者：
Perissi V
中科院分区：
文献类型：
--
作者：
Chan S;Smith E;Gao Y;Kwan J;Blum BC;Tilston-Lunel AM;Turcinovic I;Varelas X;Cardamone MD;Monti S;Emili A;Perissi V
G蛋白抑制因子2 （GPS2）是一种多功能蛋白，在脂肪、肝脏和免疫细胞的炎症和代谢中发挥重要作用。GPS2最近被确定为乳腺癌和其他恶性肿瘤中的一个显著突变基因，并被认为是一种推定的肿瘤抑制因子。然而，GPS2阻止癌症发生和/或进展的分子机制在很大程度上是未知的。在这里，我们分析了MDA-MB-231三阴性乳腺癌细胞中GPS2缺失引起的表型变化，并研究了潜在的分子机制。我们发现gps2缺失的MDA-MB-231细胞在体外表现出增加的增殖、迁移和侵袭性，并在原位异种移植小鼠模型中产生更大的肿瘤负担。gps2缺失的MBA-MB-231的转录组学、蛋白质组学和磷酸化蛋白质组学分析揭示了与细胞生长和PI3K/AKT信号通路相关的信号改变网络。GPS2调控基因表达与修饰表达组成型活性AKT的MDA-MB-231细胞重叠显示显著重叠，表明持续的AKT激活与GPS2缺失相关。因此，我们证明了与GPS2缺失相关的促癌表型通过MK2206对AKT的药理学抑制得以挽救。总之，这些观察结果证实了GPS2的肿瘤抑制作用，并揭示GPS2的缺失通过不受控制的AKT信号激活促进乳腺癌细胞增殖和肿瘤生长。此外，我们的研究指出，GPS2是对pi3k类抑制剂药物有反应的乳腺癌亚类的潜在生物标志物。
G Protein Suppressor 2 (GPS2) is a multifunctional protein that exerts important roles in inflammation and metabolism in adipose, liver, and immune cells. GPS2 has recently been identified as a significantly mutated gene in breast cancer and other malignancies and proposed to work as a putative tumor suppressor. However, molecular mechanisms by which GPS2 prevents cancer development and/or progression are largely unknown. Here, we have profiled the phenotypic changes induced by GPS2 depletion in MDA-MB-231 triple negative breast cancer cells and investigated the underlying molecular mechanisms. We found that GPS2-deleted MDA-MB-231 cells exhibited increased proliferative, migratory, and invasive properties in vitro, and conferred greater tumor burden in vivo in an orthotopic xenograft mouse model. Transcriptomic, proteomic and phospho-proteomic profiling of GPS2-deleted MBA-MB-231 revealed a network of altered signals that relate to cell growth and PI3K/AKT signaling. Overlay of GPS2-regulated gene expression with MDA-MB-231 cells modified to express constitutively active AKT showed significant overlap, suggesting that sustained AKT activation is associated with loss of GPS2. Accordingly, we demonstrate that the pro-oncogenic phenotypes associated with GPS2 deletion are rescued by pharmacological inhibition of AKT with MK2206. Collectively, these observations confirm a tumor suppressor role for GPS2 and reveal that loss of GPS2 promotes breast cancer cell proliferation and tumor growth through uncontrolled activation of AKT signaling. Moreover, our study points to GPS2 as a potential biomarker for a subclass of breast cancers that would be responsive to PI3K-class inhibitor drugs.