The Department of Pharmacology and Toxicology, College of Pharmacy University of Arizona, Tucson, Arizona, 85721, USA.
BioAgilytix, Durham, United States.
Sci Rep. 2019 Jul 25;9(1):10823. doi: 10.1038/s41598-019-46954-7.
One of the major features of cancer is Otto Warburg's observation that many tumors have increased extracellular acidification compared to healthy tissues. Since Warburg's observation, the importance of extracellular acidification in cancer is now considered a hallmark of cancer. Human MAP3K4 functions upstream of the p38 and JNK mitogen activated protein kinases (MAPKs). Additionally, MAP3K4 is required for cell migration and extracellular acidification of breast cancer cells in response to HER2/HER3 signaling. Here, we demonstrate that GIT1 interacts with MAP3K4 by immunoprecipitation, while cellular lactate production and the capacity of MCF-7 cells for anchorage independent growth in soft agar were dependent on GIT1. Additionally, we show that activation of HER2/HER3 signaling leads to reduced expression of lactate receptor (GPR81) mRNA and that both, GIT1 and MAP3K4, are necessary for constitutive expression of GPR81 mRNA. Our study suggests that targeting downstream proteins in the HER2/HER3-induced extracellular lactate signaling pathway may be a way to inhibit the Warburg Effect to disrupt tumor growth.
癌症的一个主要特征是奥托·瓦伯格（Otto Warburg）的观察结果，即许多肿瘤与健康组织相比，细胞外酸化增加。自瓦伯格（Warburg）观察以来，细胞外酸化在癌症中的重要性现在被认为是癌症的标志。人类 MAP3K4 在前体 p38 和 JNK 有丝分裂原激活蛋白激酶（MAPKs）上游起作用。此外，MAP3K4 是乳腺癌细胞响应 HER2 / HER3 信号而发生细胞迁移和细胞外酸化所必需的。在这里，我们通过免疫沉淀证明 GIT1 与 MAP3K4 相互作用，而细胞内乳酸的产生以及 MCF-7 细胞在软琼脂中锚定独立生长的能力取决于 GIT1。此外，我们表明，HER2 / HER3 信号的激活导致乳酸受体（GPR81）mRNA 的表达减少，而 GIT1 和 MAP3K4 对于 GPR81 mRNA 的组成型表达都是必需的。我们的研究表明，靶向 HER2 / HER3 诱导的细胞外乳酸信号通路中的下游蛋白可能是抑制瓦伯格效应以破坏肿瘤生长的一种方法。
