title: P2Y11 impairs cell proliferation by induction of cell cycle arrest and sensitizes endothelial cells to cisplatin-induced cell death.
abstract: Extracellular ATP mediates a wide range of physiological effects, including cell proliferation, differentiation, maturation, and migration. However, the effect of ATP on cell proliferation has been contradictory, and the mechanism is not fully understood. In the current study, we found that extracellular ATP significantly inhibited the proliferation of human umbilical vein endothelial cells (HUVECs) and human aortic endothelial cells (HAECs). Treatment with ATP did not induce cell apoptosis but instead induced cell cycle arrest in S phase. ATP induced the phosphorylation of ERK1/2, but the ERK inhibitors, U0126 and PD9809, did not regulate the inhibition of cell proliferation induced by ATP. However, ATP-induced inhibition of cell proliferation was blocked by suramin, a nonspecific antagonist of the P2Y receptors, and endothelial cells expressed P2Y11, a P2Y receptor that specifically binds ATP. Moreover, the down-regulation of P2Y11 by RNA interference not only reversed the inhibition of cell proliferation but also ameliorated cell cycle arrest in S phase. In addition, P2Y11 sensitized endothelial cells to cisplatin-induced cell death by down-regulation of the expression of Bcl-2. Taken together, these results suggest that extracellular ATP impairs cell proliferation by triggering signaling to induce cell cycle arrest and sensitizes cell to death via P2Y11 in endothelial cells.
authors.affiliation: Department of Geriatric Cardiology, Xiangya Hospital, Central South University, Changsha 410008, China.
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Xiao
authors.forename: Mei
authors.initials: M
authors.lastname: Yang
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Lv
authors.forename: Wenmeng
authors.initials: W
authors.lastname: Wang
authors.forename: Minjie
authors.initials: M
authors.lastname: Deng
authors.forename: Xueting
authors.initials: X
authors.lastname: Liu
authors.forename: Qing
authors.initials: Q
authors.lastname: He
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Chen
authors.forename: Meifang
authors.initials: M
authors.lastname: Chen
authors.forename: Li
authors.initials: L
authors.lastname: Fang
authors.forename: Xiumei
authors.initials: X
authors.lastname: Xie
authors.forename: Jinyue
authors.initials: J
authors.lastname: Hu
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology / Q000502:physiology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001011:Aorta / Q000166:cytology; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation; D004357:Drug Synergism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System; D018919:Neovascularization, Physiologic; D061251:Primary Cell Culture; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects; D014544:Uridine Triphosphate / Q000494:pharmacology / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; C109734:P2RY11 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D018048:Receptors, Purinergic P2; D000255:Adenosine Triphosphate; D002945:Cisplatin; D014544:Uridine Triphosphate