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Background Chronic stress is well known to promote tumor progression, however, the mechanisms that underlie the association of chronic stress with cancer metastasis remain elusive. Methods First, the changes in migration and invasion ability of prostate cancer cell lines PC-3 and DU145 were assessed by transwell migration assay. And HIF-1α expression of osteoblasts and the momentous proteins of epithelial-mesenchymal transition (EMT) of PC-3 and DU145 cells were examined by western blot. Then, an analysis of the main cytokines associated with bone metastasis was performed in osteoblasts by qRT-PCR. Finally, HIF-1α siRNA and inhibitor YC-1 were used to assess the reverse of isoproterenol (ISO)-induced changes of HIF-1α in osteoblasts, and β2-adrenergic receptor (β2AR) inhibitor ICI118,551 and CXCR4 inhibitor LY2510924 were used to antagonizes migration and invasion of PC-3 and DU145 cells induced by osteoblasts triggered by ISO. Results In this study, ISO, a non-selective β-adrenergic receptor (βAR) agonist, used as a pharmacological surrogate of sympathetic nerve activation induced by chronic stress, exhibits no direct effect on migration and invasion of PC-3 and DU145 prostate cancer cells. Whereas, osteoblasts pretreated with ISO promote EMT and migration as well as invasion of PC-3 and DU145 cells, which can be inhibited by β2AR inhibitor. Mechanically, ISO increases the secretion of CXCL12 via the β2AR-HIF-1α signaling in osteoblasts. Moreover, inhibiting CXCL12-CXCR4 signaling with LY2510924 blunts the effects of osteoblasts in response to ISO on EMT and migration as well as invasion of PC-3 and DU145 cells. Conclusions These findings indicate that β2AR-HIF-1α-CXCL12 signaling in osteoblasts facilitates migration and invasion as well as EMT of prostate cancer cells, and may play a potential role in affecting bone metastasis of prostate cancer.

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Background: Chronic stress is well known to promote tumor progression, however, little is known on whether neurotransmitters released after chronic stress induced sympathetic activation regulate the function of osteoblasts to affect migration and invasion of metastatic cancer cells. Methods: First, the changes in migration and invasion ability of prostate cancer cell lines PC-3 and DU145 were assessed by transwell migration assay. PC-3 and DU145 cells proliferation ability were detected by CCK-8, and HIF-1α expression of osteoblasts and the momentous proteins of epithelial-mesenchymal transition (EMT) of PC-3 and DU145 cells were examined by Western blot. Then, an analysis of the main cytokines associated with bone metastasis in osteoblasts and EMT-related biomarkers in PC-3 and DU145 cells was performed by qRT-PCR. Finally, rescue experiment was performed by using HIF-1α siRNA and inhibitor, HIF-1α overexpression plasmid, β2-adrenergic receptor (β2AR) inhibitor, CXCR4 siRNA and inhibitor. Results: In this study, isoproterenol (ISO), a non-selective β-adrenergic receptor (βAR) agonist, used as a pharmacological surrogate of sympathetic nerve activation induced by chronic stress, exhibited no direct effect on migration and invasion of PC-3 and DU145 prostate cancer cells. Whereas, osteoblasts pretreated with ISO promoted EMT and migration as well as invasion of PC-3 and DU145 cells, which was independent of promoting cell proliferation and could be inhibited by β2AR inhibitor. Mechanistically, ISO increased the secretion of CXCL12 via the β2AR-HIF-1α signaling in osteoblasts. Moreover, overexpression of HIF-1α osteoblasts promoted migration and invasion of PC-3 and DU145 cells, which was inhibited by addition of recombinant knockdown of CXCR4 in PC-3 and DU145 cells, and inhibiting CXCL12-CXCR4 signaling with LY2510924 blunted the effects of osteoblasts in response to ISO on EMT and migration as well as invasion of PC-3 and DU145 cells. Conclusions: These findings indicate that β2AR-HIF-1α-CXCL12 signaling in osteoblasts facilitates migration and invasion as well as EMT of prostate cancer cells, and may play a potential role in affecting bone metastasis of prostate cancer.