Hudson C D, Hagemann T, Mather S J, Avril N
1] Case Western Reserve University, University Hospitals Case Medical Center, Cleveland, OH, USA [2] Centre for Molecular Oncology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Centre for Molecular Oncology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Cell Death Dis. 2014 Apr 10;5(4):e1160. doi: 10.1038/cddis.2014.125.
Alterations in energy (glucose) metabolism are key events in the development and progression of cancer. In pancreatic adenocarcinoma (PDAC) cells, we investigated changes in glucose metabolism induced by resistance to the receptor tyrosine kinase inhibitor (RTKI) axitinib. Here, we show that human cell lines and mouse PDAC cell lines obtained from the spontaneous pancreatic cancer mouse model (Kras(G12D)Pdx1-cre) were sensitive to axitinib. The anti-proliferative effect was due to a G2/M block resulting in loss of 70-75% cell viability in the most sensitive PDAC cell line. However, a surviving sub-population showed a 2- to 3-fold increase in [C-14]deoxyglucose ([C-14]DG) uptake. This was sustained in axitinib-resistant cell lines, which were derived from parental PDAC. In addition to the axitinib-induced increase in [C-14]DG uptake, we observed a translocation of glucose transporter-1 (Glut-1) transporters from cytosolic pools to the cell surface membrane and a 2-fold increase in glycolysis rates measured by the extracellular acidification rate (ECAR). We demonstrated an axitinib-induced increase in phosphorylated Protein Kinase B (pAkt) and by blocking pAkt with a phosphatidylinositol-3 kinase (PI3K) inhibitor we reversed the Glut-1 translocation and restored sensitivity to axitinib treatment. Combination treatment with both axitinib and Akt inhibitor in parental pancreatic cell line resulted in a decrease in cell viability beyond that conferred by single therapy alone. Our study shows that PDAC resistance to axitinib results in increased glucose metabolism mediated by activated Akt. Combining axitinib and an Akt inhibitor may improve treatment in PDAC.
能量（葡萄糖）代谢的改变是癌症发生和发展的关键事件。在胰腺腺癌（PDAC）细胞中，我们研究了对受体酪氨酸激酶抑制剂（RTKI）阿昔替尼耐药所诱导的葡萄糖代谢变化。在此，我们表明，从自发性胰腺癌小鼠模型（Kras(G12D)Pdx1-cre）获得的人细胞系和小鼠PDAC细胞系对阿昔替尼敏感。抗增殖作用是由于G2/M期阻滞，导致最敏感的PDAC细胞系中细胞活力丧失70 - 75%。然而，一个存活的亚群显示[C-14]脱氧葡萄糖（[C-14]DG）摄取增加了2至3倍。这在源自亲代PDAC的阿昔替尼耐药细胞系中持续存在。除了阿昔替尼诱导的[C-14]DG摄取增加外，我们还观察到葡萄糖转运蛋白-1（Glut-1）从胞质池转运到细胞表面膜，并且通过细胞外酸化率（ECAR）测量的糖酵解速率增加了2倍。我们证明阿昔替尼诱导磷酸化蛋白激酶B（pAkt）增加，并且通过用磷脂酰肌醇-3激酶（PI3K）抑制剂阻断pAkt，我们逆转了Glut-1易位并恢复了对阿昔替尼治疗的敏感性。在亲代胰腺细胞系中联合使用阿昔替尼和Akt抑制剂进行治疗导致细胞活力下降，超过了单一疗法单独给予的效果。我们的研究表明，PDAC对阿昔替尼的耐药导致由活化的Akt介导的葡萄糖代谢增加。联合使用阿昔替尼和Akt抑制剂可能会改善PDAC的治疗。
