Li Wei-Hua, Qiu Ying, Zhang Hong-Quan, Tian Xin-Xia, Fang Wei-Gang
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.
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.
PLoS One. 2015 Jul 16;10(7):e0133165. doi: 10.1371/journal.pone.0133165. eCollection 2015.
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.
作为G蛋白偶联P2Y受体家族的一员，P2Y2受体可被细胞外ATP和UTP同等程度地激活。我们之前的研究已证明，细胞外ATP激活P2Y2受体可通过调控一些上皮-间质转化/侵袭相关基因（包括IL-8、E-钙黏蛋白、Snail和Claudin-1）的表达，在体外和体内促进前列腺癌细胞的侵袭和转移，且在P2Y2受体激活后，IL-8的表达变化最为显著。然而，P2Y2受体下游的信号通路以及IL-8在P2Y2介导的前列腺癌细胞侵袭中的作用仍不清楚。在此，我们发现细胞外ATP/UTP可诱导EGFR和ERK1/2激活。敲低P2Y2受体后，ATP刺激的EGFR和ERK1/2磷酸化显著受到抑制。进一步实验表明，EGFR和ERK1/2失活可减弱ATP诱导的侵袭和迁移，并抑制ATP介导的IL-8产生。此外，敲低IL-8可抑制ATP介导的前列腺癌细胞侵袭和迁移。这些发现提示，P2Y2受体与EGFR协同作用，通过ERK1/2途径上调IL-8的产生，从而促进前列腺癌细胞的侵袭和迁移。因此，阻断P2Y2-EGFR-ERK1/2途径可能为前列腺癌提供有效的治疗干预措施。
