Interestingly, previous studies have shown that apoptotic or injured tumor cells release different nucleotides as a find-me signal for phagocytic clearance. However, the surviving tumor cells can also recover from treatment, which might accelerate tumor progression. Generally, both radiotherapy and chemotherapy are administered at low doses to avoid a severe toxic reaction in normal tissues. The repopulation, progression and even metastasis of tumors after anticancer therapies such as radiotherapy, chemotherapy and surgery is well-recognized. However, the function and mechanism of extracellular UDP signaling via the P2Y 6 receptor in breast cancer metastasis remains unknown. Previous studies have shown that extracellular UDP released from damaged or stressed cells is a danger signal that promotes innate immune responses. Meanwhile, adenosine, derived from ATP hydrolysis, has been suggested to promote tumor growth and metastasis through the A 2A receptor.
For example, the anti-tumor activity of ATP was first described in pancreatic and colon cancer cells in 1983, whereas ATP was also found to be released through pannexin-1 channels as a pro-metastatic signal that permits the survival of cancer cells. Among them, the therapeutic potential of purinergic signaling for the treatment of cancer has become popular. Since the concept of purinergic signaling was first proposed in 1972, there has been growing interest in performing functional and mechanistic studies into extracellular nucleotides in the context of both physiological and pathological processes. Taken together, our study reveals a relationship between extracellular danger signals and breast cancer metastasis, which suggests the potential therapeutic significance of UDP/P2Y 6 signaling in cancer therapy. Mechanistically, the MAPKs and NF-κB signaling pathways, known to be involved in regulation of MMP-9 expression, were both activated by UDP. Furthermore, UDP-induced cell invasion was blocked by an MMP-9 inhibitor. In addition, the expression and enzyme activity of MMP-9 were both promoted by UDP and inhibited by MRS2578 or P2Y 6 shRNA. Interestingly, the endogenous agonist UDP was released significantly by doxorubicin treated cells. Similar results was also found in breast cancer cell metastasis mouse model. Furthermore, the migration and invasion of breast cancer cells was obviously increased by UDP and blocked by P2Y 6 specific inhibitor MRS2578 and P2Y 6 shRNA. We found that P2Y 6 is not only aberrantly expressed and mutated in most tumor types, but also highly correlated with poor prognosis in breast cancer patients. In this study, we demonstrate that UDP/P2Y 6 signaling facilitates breast cancer metastasis both in vitro and in vivo. Although purinergic signaling is important in regulation of immune responses, the therapeutic potential of it in the tumor microenvironment is little defined.
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