The Role of Platelet-Derived ADP and ATP in Promoting Pancreatic Cancer Cell Survival and Gemcitabine Resistance

Abstract

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 P2Y12, an ADP receptor found mainly on platelets. Thus ticagrelor, a P2Y12 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.

Human Cancer and Platelet Interaction, a Potential Therapeutic Target

“…Platelet releasates, induced by the agonists of the thrombin receptors, protease activated receptor-1 (PAR1) and PAR4 [ 37 ], promote the proliferation of MCF-7 and MDA-MB-231 breast cancer cells and angiogenesis via the phosphoinositide 3-kinase/protein kinase C (PI3K/PKC) pathway [ 38 ]. Platelet activation induced by other agonists, including the adenosine diphosphate (ADP) (through its receptor P2Y12 and P2Y1) also promotes tumor growth in ovarian cancer and pancreatic cancer [ 39 , 40 ]. Recently, the relationship between P2Y12 and cancer was reviewed by Ballerini et al indicating the important role of P2Y12 in malignant cells [ 41 ].…”

Antiplatelet Drug Ticagrelor Enhances Chemotherapeutic Efficacy by Targeting the Novel P2Y12-AKT Pathway in Pancreatic Cancer Cells

“…Previous studies have indicated that P2 signalling promotes cancer invasion and chemotherapy resistance by supporting EMT in cancer cells [45]. Signalling through ATP, for example, can promote the upregulation of the mesenchymal transcriptional factor SNAIL1 in prostate cancer cells [46], whereas we previously demonstrated that ADP signalling promotes SLUG upregulation in PDAC cells [9]. SNAIL1 and SLUG (SNAIL2) belong to a family of mesenchymal transcriptional factors that can modulate EMT and chemotherapy resistance through controlling the expression of cell adhesion proteins (e.g., E-cadherin), other mesenchymal transcriptional factors (e.g., ZEB1) or drug metabolising enzymes and drug transporter proteins (e.g., CDD, ENT1) [5].…”

“…However, its short-term activity and recent FDA approval of a reversal agent may make it a more favourable choice than other antiplatelet agents in the context of cancer-associated thrombosis [5]. It is important to mention that several clinical trials failed to show a survival benefit of using anticoagulants for the primary or secondary prevention of venous thrombosis in pancreatic cancer, despite a reduction in the incidence of thrombotic events at the expense of the bleeding risk [6][7][8][9]. Therefore, antiplatelet medication, such as ticagrelor, may provide an alternative strategy to mitigate cancer-associated thrombosis, as well as conferring a direct anti-tumour activity, as highlighted by our study.…”

“…We previously showed that platelets promote CDD expression in pancreatic cancer cells [9]. CDD is known to deactivate gemcitabine and increase drug resistance.…”

“…Moreover, activation of the epithelial-mesenchymal transition (EMT), a cell developmental programme, in cancer cells further promotes chemotherapy resistance in PDAC [5]. We recently showed that platelet-derived factors, predominantly ADP/ATP, were responsible for an increased level of SLUG, an EMT transcriptional factor, which regulated the expression of cytidine deaminase (CDD) and equiliberative nucleoside transporter 1 (ENT1), and contributed to gemcitabine resistance [9].…”