Abstract
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.
Highlights
Extracellular acidification is frequently increased in cancer due to a shift from aerobic to anaerobic glycolysis which results in increased lactate production and secretion[1]
We hypothesized that the increase in extracellular acidification was driven by the signaling of a complex downstream of HER3 comprised of MAP3K4 and other proteins resulting in increased glycolysis and lactic acid secretion
We reported that MAP3K4 associates with tyrosine phosphorylated HER3 in response to HRG stimulation of MCF-7 and T-47D breast cancer cells and, we showed that HER2 activity was required for the association between MAP3K4 and HER3, but HER2 was not present in this complex of proteins[24]
Summary
Extracellular acidification is frequently increased in cancer due to a shift from aerobic to anaerobic glycolysis which results in increased lactate production and secretion[1]. In vitro studies by Roland et al with pancreatic cancer cells have shown that addition of lactate to the culture media induced the expression of genes involved in lactate metabolism such as MCT1, MCT4, CD147, and peroxisome proliferator activated receptor γ coactivator 1-α (PGC-1α). Roland et al reported that siRNA knockdown of GPR81 results in decreased survival of pancreatic cancer cells cultured in low glucose supplemented with lactate[10] These findings indicate that lactate, presumably by functioning as a GPR81 ligand, can function as a signaling molecule in cancer. We showed that MAP3K4 is regulated through activation of cytokine receptor [i.e., IFNγ18] and the angiotensin II G protein coupled receptor[19] These results demonstrate the importance of MAP3K4 in diverse signaling pathways through both scaffolding and catalytic activities. GIT1 has been shown to play an important role as a scaffold in both the RTK pathway and MAPK pathway[21,22,23]
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