Caveolin-1-LRP6 signaling module stimulates aerobic glycolysis in prostate cancer.
Caveolin-1-LRP6 signaling module stimulates aerobic glycolysis in prostate cancer.
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DOI：
10.1158/0008-5472.can-12-3040
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发表时间：
2013-03-15
期刊：
影响因子：
11.2
通讯作者：
Thompson TC
中科院分区：
文献类型：
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作者：
Tahir SA;Yang G;Goltsov A;Song KD;Ren C;Wang J;Chang W;Thompson TC
Caveolin 1 (Cav-1) 是一种质膜相关蛋白，能够以上下文相关的方式调节信号活动。据报道，Cav-1 和低密度脂蛋白受体相关蛋白 6 (LRP6) 之间的相互作用对于 Wnt-β-连环蛋白 (β-cat) 信号传导的调节非常重要。 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。我们发现人原发性前列腺癌和转移组织以及 PC-3 细胞中 Cav-1 和 LRP6 表达呈正相关。 Cav-1 对 Wnt-β-cat 信号传导和 c-Myc 水平的刺激与 LNCaP、PC-3 和 DU145 前列腺癌细胞中的 LRP6 表达呈正相关。重要的是，LRP6 以及较小程度上的 Cav-1 被发现可以刺激有氧糖酵解。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 信号传导。我们进一步表明，Cav-1 和 LRP6 通过刺激 IGF-IR/IR 信号传导对 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 相互作用产生一个集成信号模块，导致 IGF-IR/IR 激活，并刺激 Akt-mTORC1 信号传导和前列腺癌中的有氧糖酵解。
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 demonstrate 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.