The role of platelet-derived ADP and ATP in promoting pancreatic cancer cell survival and gemcitabine resistance
MetadataShow full item record
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 12 , an ADP receptor found mainly on platelets. Thus ticagrelor, a P2Y 12 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. © 2017 by the authors.
Showing items related by title, author, creator and subject.
Edling, C.; Selvaggi, F.; Buus, R.; Maffucci, T.; Di Sebastiano, P.; Friess, H.; Innocenti, P.; Kocher, H.; Falasca, Marco (2010)Purpose: Phosphoinositide 3-kinase (PI3K) signaling is well established as important in cancer. To date most studies have been focused on the PI3K/p110a isoform, which has been found to be mutated in several different ...
Introduction of WT-TP53 into pancreatic cancer cells alters sensitivity to chemotherapeutic drugs, targeted therapeutics and nutraceuticalsAbrams, S.; Lertpiriyapong, K.; Yang, L.; Martelli, A.; Cocco, L.; Ratti, S.; Falasca, Marco; Murata, R.; Rosalen, P.; Lombardi, P.; Libra, M.; Candido, S.; Montalto, G.; Cervello, M.; Steelman, L.; McCubrey, J. (2018)© 2018 Elsevier Ltd Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, highly metastatic malignancy and accounts for 85% of pancreatic cancers. PDAC patients have poor prognosis with a five-year survival of only ...
Neutrophil extracellular traps induce aggregation of washed human platelets independently of extracellular DNA and histonesElaskalani, O.; Abdol Razak, N.; Metharom, Pat (2018)© 2018 The Author(s). Background: The release of neutrophil extracellular traps (NETs), a mesh of DNA, histones and neutrophil proteases from neutrophils, was first demonstrated as a host defence against pathogens. Recently ...