P2Y receptors for extracellular nucleotides: Contributions to cancer progression and therapeutic implications

Abstract

Purinergic receptors for extracellular nucleotides and nucleosides contribute to a vast array of cellular and tissue functions, including cell proliferation, intracellular and transmembrane ion flux, immunomodulation and thrombosis. In mammals, the purinergic receptor system is composed of G protein-coupled P1 receptors A₁, A_2A, A_2B and A₃ for extracellular adenosine, P2X1-7 receptors that are ATP-gated ion channels and G protein-coupled P2Y_{1,2,4,6,11,12,13 and 14} receptors for extracellular ATP, ADP, UTP, UDP and/or UDP-glucose. Recent studies have implicated specific P2Y receptor subtypes in numerous oncogenic processes, including cancer tumorigenesis, metastasis and chemotherapeutic drug resistance, where G protein-mediated signaling cascades modulate intracellular ion concentrations and activate downstream protein kinases, Src family kinases as well as numerous mitogen-activated protein kinases. We are honored to contribute to this special issue dedicated to the founder of the field of purinergic signaling, Dr. Geoffrey Burnstock, by reviewing the diverse roles of P2Y receptors in the initiation, progression and metastasis of specific cancers with an emphasis on pharmacological and genetic strategies employed to delineate cell-specific and P2Y receptor subtype-specific responses that have been investigated using in vitro and in vivo cancer models. We further highlight bioinformatic and empirical evidence on P2Y receptor expression in human clinical specimens and cover clinical perspectives where P2Y receptor-targeting interventions may have therapeutic relevance to cancer treatment.

Keywords: Cancer; Extracellular nucleotides; Metastasis; P2Y receptors; Proliferation; Purinergic receptors.

Figure 1.. Extracellular purinome signal integration.

Cell-specific responses to extracellular nucelotides result from the combined activation of P2X ATP-gated ion channels, P2Y G protein-coupled nucleotide receptors and P1 G protein-coupled adenosine receptors. Through the action of ectonucleotide triphosphate diphosphohydrolases (ENTPDs) and the ecto-5’-nucleotidase CD73, extracellular ATP is broken down to generate nucleotide di- and monophosphates and adenosine to shift the purinergic response from ATP-activated P2X and P2Y receptors to UDP and ADP-activated P2Y receptors and eventually to P1 adenosine receptors. Adenosine is then recycled through cell-surface nucleoside transporters that terminate the extracellular signal. Cell- and tissue-specific expression of P2R, P1R, ENTPD, CD73 and nucleoside transporters make up the local extracellular purinome and intracellular integration of ion flux and G protein-mediated signaling cascades determines the overall cellular response. Figure created with BioRender.com.