Medical University of Vienna, Department of Surgery, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
Biochem Biophys Res Commun. 2010 Mar 12;393(3):414-9. doi: 10.1016/j.bbrc.2010.02.009. Epub 2010 Feb 6.
Acidosis commonly observed in solid tumors like pancreatic cancer promotes genetic instability and selection of a more malignant phenotype of cancer cells. Overexpression or activation of integral membrane proteins mediating H+ efflux may contribute to extracellular acidification. Neurotensin (NT) induces intracellular alkalinization and stimulates interleukin-8 production in pancreatic cancer cells and, as demonstrated here, the stable NT analog Lys(8)-psi-Lys(9)NT(8-13) enhances the amiloride-sensitive, Na+-dependent transmembrane H+ flux by a factor of 2.05+/-0.28 and 2.69+/-0.07 in BxPC-3 and PANC-1 pancreatic cancer cells, respectively, by phosphorylation of the Na+/H+ exchanger 1 (NHE1). Human genome-wide gene expression analysis was performed to detect effects of Lys(8)-psi-Lys(9)NT(8-13) on BxPC-3 cells. Results indicated upregulation of genes involved in regulation of NHE1, hypoxic response and glycolysis in response to Lys(8)-psi-Lys(9)NT(8-13) even under normoxic conditions. Therefore, our findings suggest that growth factors like NT may be implicated in the early progression of pancreatic cancer by localized acidification and induction of an aerobic glycolytic phenotype with higher metastatic potential in small cell aggregates.
在胰腺癌等实体瘤中常观察到的酸中毒可促进癌细胞遗传不稳定性和更恶性表型的选择。介导 H+外排的完整膜蛋白的过表达或激活可能有助于细胞外酸化。神经降压素（NT）可诱导胰腺癌细胞内碱化并刺激白细胞介素-8 的产生，正如这里所证明的，稳定的 NT 类似物 Lys(8)-psi-Lys(9)NT(8-13) 通过磷酸化钠/氢交换器 1 (NHE1)，使 BxPC-3 和 PANC-1 胰腺癌细胞中阿米洛利敏感的、Na+依赖性跨膜 H+流分别增加 2.05+/-0.28 和 2.69+/-0.07 倍。进行了人类全基因组基因表达分析，以检测 Lys(8)-psi-Lys(9)NT(8-13)对 BxPC-3 细胞的影响。结果表明，即使在正常氧条件下，Lys(8)-psi-Lys(9)NT(8-13) 也可上调与 NHE1、缺氧反应和糖酵解调节相关的基因。因此，我们的发现表明，生长因子（如 NT）可能通过局部酸化和诱导具有更高转移潜能的有氧糖酵解表型而参与胰腺癌的早期进展，在小细胞聚集体中。
