ATP Inhibits Breast Cancer Migration and Bone Metastasis through Down-Regulation of CXCR4 and Purinergic Receptor P2Y11

Abstract

ATP released by bone osteocytes is shown to activate purinergic signaling and inhibit the metastasis of breast cancer cells into the bone. However, the underlying molecular mechanism is not well understood. Here, we demonstrate the important roles of the CXCR4 and P2Y11 purinergic receptors in mediating the inhibitory effect of ATP on breast cancer cell migration and bone metastasis. Wound-healing and transwell migration assays showed that non-hydrolysable ATP analogue, ATPγS, inhibited migration of bone-tropic human breast cancer cells in a dose-dependent manner. BzATP, an agonist for P2X7 and an inducer for P2Y11 internalization, had a similar dose-dependent inhibition on cell migration. Both ATPγS and BzATP suppressed the expression of CXCR4, a chemokine receptor known to promote breast cancer bone metastasis, and knocking down CXCR4 expression by siRNA attenuated the inhibitory effect of ATPγS on cancer cell migration. While a P2X7 antagonist A804598 had no effect on the impact of ATPγS on cell migration, antagonizing P2Y11 by NF157 ablated the effect of ATPγS. Moreover, the reduction in P2Y11 expression by siRNA decreased cancer cell migration and abolished the impact of ATPγS on cell migration and CXCR4 expression. Similar to the effect of ATPγS on cell migration, antagonizing P2Y11 inhibited bone-tropic breast cancer cell migration in a dose-dependent manner. An in vivo study using an intratibial bone metastatic model showed that ATPγS inhibited breast cancer growth in the bone. Taken together, these results suggest that ATP inhibits bone-tropic breast cancer cells by down-regulating the P2Y11 purinergic receptor and the down-regulation of CXCR4 expression.

P2X7 receptor involved in antitumor activity of atractylenolide I in human cervical cancer cells

“…BzATP is the agonist to active P2X7 receptor, theoretically which would be harmful for the treatment of cancer in that increasing evidence demonstrated that suppression of high concentration of ATP in tumor microenvironment and the activation of P2X7 is recognized as a promising strategy for the treatment of different tumors [ 12 , 18 , 20 , 38 , 39 ]. However, ATP is considered a double-edged sword in cancer [ 40 , 41 ] and BzATP could inhibit breast cancer cell migration [ 42 ]. It indicated that both the agonist (BzATP) and antagonist (JNJ) of P2X7 receptor would be useful to inhibit the proliferation of human cervical cancer.…”

A Systematic Review of the Expression, Signalling and Function of P2 Receptors in Primary Bone Cancer

“…In other cancers, the role of P2RY11 is gradually developing. P2RY11 was shown to be highly expressed in hepatocellular carcinoma tissue compared to normal tissue and promotes migration in vitro [76], this was similarly the case in breast cancer where siRNA knockdown of P2RY11 inhibited cell migration, as did NF157 which reduced breast cancer cell migration in a dose-dependent manner [77]. P2RY11 expression and function has not been explored in any other PBC models and therefore it could provide a novel target for OS or Ewing's sarcoma where NF157 could be used.…”

Novel insights into osteocyte and inter-organ/tissue crosstalk

“…Primary bone tumors are relatively rare, but because of the highly vascularized and metastatic environment (TGFβ-rich calcified matrix), bone tissue is the third most common site of solid tumor metastasis, with up to 70% of metastatic breast and prostate cancer patients harboring bone metastasis, leading to shortened survival time and serious bone complications during the remaining lifespan ( 91 – 94 ). Distant metastasis such as bone tissue is considered one of the primary causes of treatment failure in advanced breast cancer ( 5 , 55 ). Among all the bone cells, OCY seems less affected by metastasizing cancer cells because they are further away from the actively metabolized bone marrow.…”