Abstract
Simple SummaryThe skeleton is the most frequent metastatic site for advanced breast cancer, and complications resulting from breast cancer metastasis are a leading cause of death in patients. Therefore, the discovery of new targets for the treatment of breast cancer bone metastasis is of great significance. ATP released by bone osteocytes is shown to activate purinergic signaling and inhibit the metastasis of breast cancer cells in the bone. The aim of our study was to unveil the underlying molecular mechanism of ATP and purinergic signaling in inhibiting the bone metastasis of breast cancer cells. We demonstrated that CXCR4 and P2Y11 are key factors in regulating this process, and understanding of this important mechanism will aid in identifying new targets and developing first-in-class therapeutics.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.
Highlights
Breast cancer is the most common malignancy among women worldwide [1]
We have previously shown that ATP release by connexin hemichannels in osteocytes suppresses breast cancer cell migration and bone metastasis [8,9]
We showed that downregulation of CXCR4 expression was one of the mechanisms for the inhibitory effect of ATP on bone tropic cancer cell migration
Summary
Breast cancer is the most common malignancy among women worldwide [1]. Breast cancer patients’ overall survival has improved in recent decades, it is still the primary cause of cancer deaths in women. Distant metastasis is considered the primary cause of treatment failure. Bone is the most common metastatic site for breast cancer, and bone metastases cause significant complications, which greatly compromise the quality of life and shorten survival time [2,3]. In addition to its role as an intracellular energy source, similar to other cell types, extracellular ATP in cancer cells acts as a ligand that binds to purinergic receptors and modulates intracellular signaling mechanisms [4].
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