Elaskalani Omar, Falasca Marco, Moran Niamh, Berndt Michael C, Metharom Pat
Platelet Research Laboratory, School of Biomedical Sciences, Curtin Health and Innovation Research Institute, Faculty of Health Sciences, Curtin University, Bentley, WA 6102, Australia.
Metabolic Signalling Group, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia.
Cancers (Basel). 2017 Oct 24;9(10):142. doi: 10.3390/cancers9100142.
Platelets have been demonstrated to be vital in cancer epithelial-mesenchymal transition (EMT), an important step in metastasis. Markers of EMT are associated with chemotherapy resistance. However, the association between the development of chemoresistance, EMT, and the contribution of platelets to the process, is still unclear. Here we report that platelets regulate the expression of (1) human equilibrative nucleoside transporter 1 (hENT1) and (2) cytidine deaminase (CDD), markers of gemcitabine resistance in pancreatic cancer. Human ENT1 (hENT1) is known to enable cellular uptake of gemcitabine while CDD deactivates gemcitabine. Knockdown experiments demonstrate that Slug, a mesenchymal transcriptional factor known to be upregulated during EMT, regulates the expression of hENT1 and CDD. Furthermore, we demonstrate that platelet-derived ADP and ATP regulate Slug and CDD expression in pancreatic cancer cells. Finally, we demonstrate that pancreatic cancer cells express the purinergic receptor P2Y, an ADP receptor found mainly on platelets. Thus ticagrelor, a P2Y inhibitor, was used to examine the potential therapeutic effect of an ADP receptor antagonist on cancer cells. Our data indicate that ticagrelor negated the survival signals initiated in cancer cells by platelet-derived ADP and ATP. In conclusion, our results demonstrate a novel role of platelets in modulating chemoresistance in pancreatic cancer. Moreover, we propose ADP/ATP receptors as additional potential drug targets for treatment of pancreatic cancer.
血小板已被证明在癌症上皮-间质转化（EMT）中起着至关重要的作用，EMT是转移过程中的重要一步。EMT的标志物与化疗耐药性相关。然而，化疗耐药性的发展、EMT以及血小板在这一过程中的作用之间的关联仍不清楚。在此我们报告，血小板可调节（1）人类平衡核苷转运体1（hENT1）和（2）胞苷脱氨酶（CDD）的表达，这两种蛋白是胰腺癌中吉西他滨耐药性的标志物。已知人类ENT1（hENT1）可使细胞摄取吉西他滨，而CDD可使吉西他滨失活。敲低实验表明，Slug（一种已知在EMT过程中上调的间充质转录因子）可调节hENT1和CDD的表达。此外，我们证明血小板衍生的ADP和ATP可调节胰腺癌细胞中Slug和CDD的表达。最后，我们证明胰腺癌细胞表达嘌呤能受体P2Y，这是一种主要在血小板上发现的ADP受体。因此，使用替格瑞洛（一种P2Y抑制剂）来研究ADP受体拮抗剂对癌细胞的潜在治疗效果。我们的数据表明，替格瑞洛可消除血小板衍生的ADP和ATP在癌细胞中引发的存活信号。总之，我们的结果证明了血小板在调节胰腺癌化疗耐药性方面的新作用。此外，我们提出ADP/ATP受体作为治疗胰腺癌的额外潜在药物靶点。
