Department of Genitourinary Medical Oncology-Research, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer Res. 2013 Mar 15;73(6):1900-11. doi: 10.1158/0008-5472.CAN-12-3040. Epub 2013 Jan 9.
Caveolin 1 (Cav-1) is a plasma membrane-associated protein with the capacity to modulate signaling activities in a context-dependent fashion. Interactions between Cav-1 and low-density lipoprotein receptor-related protein 6 (LRP6) were reported to be important for the regulation of Wnt-β-catenin (β-cat) signaling. Cav-1 also interacts with insulin and IGF-I receptors (IGF-IR/IR) and can stimulate IR kinase activities. We found positive correlation between Cav-1 and LRP6 expression in both human primary prostate cancer and metastasis tissues and in PC-3 cells. Cav-1 stimulation of Wnt-β-cat signaling and c-Myc levels was positively associated with LRP6 expression in LNCaP, PC-3, and DU145 prostate cancer cells. Importantly, LRP6 and, to a lesser extent, Cav-1 were found to stimulate aerobic glycolysis. These activities were positively associated with the expression of HK2 and Glut3 and shown to be dependent on Akt signaling by both gene knockdown and chemical inhibition methods. We further showed that Cav-1 and LRP6 exert their effects on Akt and glycolytic activities by stimulating IGF-IR/IR signaling. Overall, our results show that Cav-1 interacts with LRP6 to generate an integrated signaling module that leads to the activation of IGF-IR/IR and results in stimulation of Akt-mTORC1 signaling and aerobic glycolysis in prostate cancer.
窖蛋白 1（Cav-1）是一种与质膜相关的蛋白，具有以依赖于上下文的方式调节信号转导活性的能力。已经报道窖蛋白 1（Cav-1）与低密度脂蛋白受体相关蛋白 6（LRP6）之间的相互作用对于调节 Wnt-β-连环蛋白（β-cat）信号转导很重要。窖蛋白 1（Cav-1）还与胰岛素和 IGF-I 受体（IGF-IR/IR）相互作用，并可以刺激 IR 激酶活性。我们发现，在人原发性前列腺癌和转移组织以及 PC-3 细胞中，Cav-1 和 LRP6 的表达之间存在正相关。在 LNCaP、PC-3 和 DU145 前列腺癌细胞中，Cav-1 对 Wnt-β-cat 信号转导和 c-Myc 水平的刺激与 LRP6 的表达呈正相关。重要的是，LRP6 并且在较小程度上，Cav-1 被发现刺激有氧糖酵解。这些活性与 HK2 和 Glut3 的表达呈正相关，并且通过基因敲低和化学抑制方法显示依赖于 Akt 信号转导。我们进一步表明，Cav-1 和 LRP6 通过刺激 IGF-IR/IR 信号转导对 Akt 和糖酵解活性发挥作用。总的来说，我们的结果表明，Cav-1 与 LRP6 相互作用，形成一个整合的信号模块，导致 IGF-IR/IR 的激活，并导致前列腺癌细胞中 Akt-mTORC1 信号转导和有氧糖酵解的刺激。
