Abstract
Although purinergic signaling is important in regulation of immune responses, the therapeutic potential of it in the tumor microenvironment is little defined. In this study, we demonstrate that UDP/P2Y6 signaling facilitates breast cancer metastasis both in vitro and in vivo. We found that P2Y6 is not only aberrantly expressed and mutated in most tumor types, but also highly correlated with poor prognosis in breast cancer patients. Furthermore, the migration and invasion of breast cancer cells was obviously increased by UDP and blocked by P2Y6 specific inhibitor MRS2578 and P2Y6 shRNA. Similar results was also found in breast cancer cell metastasis mouse model. Interestingly, the endogenous agonist UDP was released significantly by doxorubicin treated cells. In addition, the expression and enzyme activity of MMP-9 were both promoted by UDP and inhibited by MRS2578 or P2Y6 shRNA. Furthermore, UDP-induced cell invasion was blocked by an MMP-9 inhibitor. Mechanistically, the MAPKs and NF-κB signaling pathways, known to be involved in regulation of MMP-9 expression, were both activated by UDP. Taken together, our study reveals a relationship between extracellular danger signals and breast cancer metastasis, which suggests the potential therapeutic significance of UDP/P2Y6 signaling in cancer therapy.
Highlights
Since the concept of purinergic signaling was first proposed in 1972 [1], there has been growing interest in performing functional and mechanistic studies into extracellular nucleotides in the context of both physiological and pathological processes
The function and mechanism of extracellular UDP signaling via the P2Y6 receptor in breast cancer metastasis remains unknown
T47D cells with UDP, the migration in both scratch and Transwell assays was little enhanced (Supplementary Figure S1A and S1B). These results show the inductive effect of UDP/P2Y6 in breast cancer cell migration and invasion
Summary
Since the concept of purinergic signaling was first proposed in 1972 [1], there has been growing interest in performing functional and mechanistic studies into extracellular nucleotides in the context of both physiological and pathological processes. The therapeutic potential of purinergic signaling for the treatment of cancer has become popular [2]. Adenosine, derived from ATP hydrolysis, has been suggested to promote tumor growth [5] and metastasis through the A2A receptor [6]. Previous studies have shown that extracellular UDP released from damaged or stressed cells is a danger signal that promotes innate immune responses [7, 8]. The function and mechanism of extracellular UDP signaling via the P2Y6 receptor in breast cancer metastasis remains unknown
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
