title: P2Y2 Receptor and EGFR Cooperate to Promote Prostate Cancer Cell Invasion via ERK1/2 Pathway.
abstract: As one member of G protein-coupled P2Y receptors, P2Y2 receptor can be equally activated by extracellular ATP and UTP. Our previous studies have proved that activation of P2Y2 receptor by extracellular ATP could promote prostate cancer cell invasion and metastasis in vitro and in vivo via regulating the expressions of some epithelial-mesenchymal transition/invasion-related genes (including IL-8, E-cadherin, Snail and Claudin-1), and the most significant change in expression of IL-8 was observed after P2Y2 receptor activation. However, the signaling pathway downstream of P2Y2 receptor and the role of IL-8 in P2Y2-mediated prostate cancer cell invasion remain unclear. Here, we found that extracellular ATP/UTP induced activation of EGFR and ERK1/2. After knockdown of P2Y2 receptor, the ATP -stimulated phosphorylation of EGFR and ERK1/2 was significantly suppressed. Further experiments showed that inactivation of EGFR and ERK1/2 attenuated ATP-induced invasion and migration, and suppressed ATP-mediated IL-8 production. In addition, knockdown of IL-8 inhibited ATP-mediated invasion and migration of prostate cancer cells. These findings suggest that P2Y2 receptor and EGFR cooperate to upregulate IL-8 production via ERK1/2 pathway, thereby promoting prostate cancer cell invasion and migration. Thus blocking of the P2Y2-EGFR-ERK1/2 pathway may provide effective therapeutic interventions for prostate cancer.
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Health Science Center, Beijing, 100191, China; Department of Pathology, Peking University Health Science Center, Beijing, 100191, China.
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Li
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Health Science Center, Beijing, 100191, China; Department of Pathology, Peking University Health Science Center, Beijing, 100191, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Health Science Center, Beijing, 100191, China; Department of Anatomy, Histology and Embryology, Peking University Health Science Center, Beijing, 100191, China.
authors.forename: Hong-Quan
authors.initials: HQ
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Health Science Center, Beijing, 100191, China; Department of Pathology, Peking University Health Science Center, Beijing, 100191, China.
authors.forename: Xin-Xia
authors.initials: XX
authors.lastname: Tian
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Health Science Center, Beijing, 100191, China; Department of Pathology, Peking University Health Science Center, Beijing, 100191, China.
authors.forename: Wei-Gang
authors.initials: WG
authors.lastname: Fang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016209:Interleukin-8 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011467:Prostate / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D020239:Receptor Cross-Talk; D058473:Receptors, Purinergic P2Y2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014544:Uridine Triphosphate / Q000378:metabolism / Q000494:pharmacology
chemical_list: D016209:Interleukin-8; D034741:RNA, Small Interfering; D058473:Receptors, Purinergic P2Y2; D000255:Adenosine Triphosphate; C512478:EGFR protein, human; D066246:ErbB Receptors; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D014544:Uridine Triphosphate